U.S. patent application number 11/711965 was filed with the patent office on 2007-11-29 for controlled agglomeration.
This patent application is currently assigned to LifeCycle Pharma A/S. Invention is credited to Anders Burr, Michiel Onne Elema, Jannie Egeskov Holm, Per Holm, Birgitte Mollgaard, Kirsten Schultz.
Application Number | 20070275074 11/711965 |
Document ID | / |
Family ID | 8160610 |
Filed Date | 2007-11-29 |
United States Patent
Application |
20070275074 |
Kind Code |
A1 |
Holm; Per ; et al. |
November 29, 2007 |
Controlled agglomeration
Abstract
A process for the preparation of a particulate material by a
controlled agglomeration method, i.e. a method that enables a
controlled growth in particle size. The method is especially
suitable for use in the preparation of pharmaceutical compositions
containing a therapeutically and/or prophylactically active
substance which has a relatively low aqueous solubility and/or
which is subject to chemical decomposition. The process comprising
i) spraying a first composition comprising a carrier, which has a
melting point of about 5.degree. C. or more which is present in the
first composition in liquid form, on a second composition
comprising a material in solid form, the second composition having
a temperature of at the most a temperature corresponding to the
melting point of the carrier and/or the carrier composition and ii)
mixing or others means of mechanical working the second composition
onto which the first composition is sprayed to obtain the
particulate material.
Inventors: |
Holm; Per; (Vanlose, DK)
; Burr; Anders; (Allerod, DK) ; Elema; Michiel
Onne; (Copenhagen, DK) ; Mollgaard; Birgitte;
(Virum, DK) ; Holm; Jannie Egeskov; (Valby,
DK) ; Schultz; Kirsten; (Roskilde, DK) |
Correspondence
Address: |
EDWARDS ANGELL PALMER & DODGE LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Assignee: |
LifeCycle Pharma A/S
Horsholm
DK
DK-2970
|
Family ID: |
8160610 |
Appl. No.: |
11/711965 |
Filed: |
February 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10482558 |
Jul 26, 2004 |
7217431 |
|
|
11711965 |
Feb 27, 2007 |
|
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Current U.S.
Class: |
424/489 ;
514/772; 514/772.4; 514/781 |
Current CPC
Class: |
A61K 9/1623 20130101;
B01J 2/006 20130101; A61K 9/1682 20130101; A61K 9/1694 20130101;
Y10T 428/29 20150115; Y10T 428/2998 20150115; A61K 9/2009 20130101;
Y10T 428/2982 20150115; A61K 9/1641 20130101; Y10T 428/2991
20150115; A61K 9/1611 20130101; A61K 9/2031 20130101; Y10T
428/24901 20150115; A61K 9/1652 20130101; B01J 2/02 20130101; Y10T
428/24868 20150115; A61K 9/2018 20130101 |
Class at
Publication: |
424/489 ;
514/772; 514/772.4; 514/781 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 47/06 20060101 A61K047/06; A61K 47/26 20060101
A61K047/26; A61K 47/46 20060101 A61K047/46 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 6, 2001 |
DK |
PA 2001 01071 |
Jul 5, 2002 |
DK |
PCT/DK02/00472 |
Claims
1-56. (canceled)
57. A method for preparing particulate material, comprising:
spraying a first composition on a second composition, wherein the
first composition comprises one or more therapeutically or
prophylactically active substances and a carrier in liquid form,
wherein the carrier has a melting point of at least about 5.degree.
C., and the second composition comprises a material in solid form
at a temperature corresponding to or below the melting point of the
first composition, and agglomerating the composition by mixing the
second composition onto which the first composition is sprayed to
obtain particulate material.
58. The method of claim 57, wherein the therapeutically or
prophylactically active substance has an aqueous solubility of at
most about 3 mg/ml at 25.degree. C. and a pH of about 7.4.
59. The method of claim 57, wherein the therapeutically active or
prophylactic substance has an aqueous solubility of at most about 1
mg/ml at about 25.degree. C. and a pH of about 7.4.
60. The method of claim 57, wherein the therapeutically or
prophylactically active substance has an aqueous solubility of at
most about 0.01 mg/ml at about 25.degree. C. and a pH of about
7.4.
61. The method of claim 57, wherein the carrier has a melting point
of about 10.degree. C. or more.
62. The method of claim 57, wherein the carrier has a melting point
of at least about 20.degree. C.
63. The method of claim 57, wherein the carrier has a melting point
of at least about 25.degree. C.
64. The method of claim 57, wherein the temperature of the second
composition is at least about 2.degree. C. below the melting point
temperature of the carrier or the first composition.
65. The method of claim 57, wherein the temperature of the second
composition is at least about 5.degree. C. below the melting point
temperature of the carrier or the first composition.
66. The method of claim 57, wherein the temperature of the second
composition is at least about 10.degree. C. below the melting point
temperature of the carrier or the first composition.
67. The method of claim 57, where the mixing is in a high shear
mixer, a low shear mixer, or a fluid bed.
68. The method of claim 57, wherein the mixing is in a fluid bed
and the spraying of the carrier composition is performed on the
second composition in a fluidized state.
69. The method of claim 57, wherein the spraying is performed
through a spraying device equipped with temperature controlling
means.
70. The method of claim 57, wherein the particles have a geometric
weight mean diameter d.sub.gw of at least about 10 micrometer.
71. The method of claim 57, wherein the particles have a geometric
weight mean diameter d.sub.gw of between about 20 micrometer and
about 2000 micrometer.
72. The method of claim 57, wherein the concentration of the
carrier in the particles is from about 5 to about 95% v/v.
73. The method of claim 57, wherein the first composition is
liquidized by heating the carrier or the first composition to a
temperature, which causes the carrier or the carrier composition to
melt.
74. The method of claim 74, wherein the liquidized carrier or
carrier composition has a viscosity of at most about 800 mPas at a
temperature of at most about 100.degree. C.
75. The method of claim 57, wherein the first composition is
essentially non-aqueous.
76. The method of claim 57, wherein the first composition comprises
at most about 20% w/w water.
77. The method of claim 57, wherein the carrier has a melting point
of at most about 300.degree. C.
78. The method of claim 57, wherein the carrier is a hydrophilic
carrier, a hydrophobic carrier, a surfactant or a mixture
thereof.
79. The method of claim 78, wherein the carrier is selected from
one or more of polyether glycols; polyoxyethylenes,
polyoxypropylenes; poloxamers and mixtures thereof.
80. The method of claim 78, wherein the carrier is selected from
one or more of polyethylene glycol and polypropylene glycol.
81. The method of claim 78, wherein the carrier is selected from
one or more of xylitol, sorbitol, potassium sodium tartrate,
sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid,
hydroquinon monomethyl ether, sodium acetate, ethyl fumarate,
myristic acid, citric acid; polyglycolized glycerides Gelucire
50/13, Gelucire 44114, Gelucire 50/10, Gelucire 62/05; Sucro-ester
7, Sucro-ester 11, Sucro-ester 15, maltose, mannitol and mixtures
thereof.
82. The method of claim 78, wherein the carrier is selected from
one or more of straight chain saturated hydrocarbons, sorbitan
esters paraffins; fats and oils, cacao butter, beef tallow, lard,
polyether glycol esters; higher fatty acids, stearic acid, myristic
acid, palmitic acid, higher alcohols, cetanol, stearyl alcohol, low
melting point waxes, glyceryl monostearate, hydrogenated tallow,
myristyl alcohol, stearyl alcohol, substituted and/or unsubstituted
monoglycerides, substituted and/or unsubstituted diglycerides,
substituted and/or unsubstituted triglycerides, yellow beeswax,
white beeswax, carnauba wax, castor wax, japan wax, acetylate
monoglycerides; NVP polymers, PVP polymers, and acrylic
polymers.
83. The method of claim 57, wherein the carrier is polyethylene
glycol having an average molecular weight from between about 400 to
about 35,000.
84. The method of claim 57, wherein the carrier is selected from
the group consisting of polyethylene glycol 1,000, polyethylene
glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000,
polyethylene glycol 5,000, polyethylene glycol 6000, polyethylene
glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000
polyethylene glycol 10,000, polyethylene glycol 15,000,
polyethylene glycol 20,000, and polyethylene glycol 35,000.
85. The method of claim 57, wherein the carrier is polyethylene
oxide having a molecular weight of from between about 2,000 to
about 7,000,000.
86. The method of claim 57, wherein the carrier is a poloxamer.
87. The method of claim 57, wherein the carrier is selected from
the group consisting of Poloxamer 188, Poloxamer 237, Poloxamer 338
and Poloxamer 407.
88. The method of claim 57, wherein the carrier is selected from
the group consisting of sorbitan esters, sorbitan. di-isostearate,
sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate,
sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate,
sorbitan sesqui-isostearate, sorbitan sesquloleate, sorbitan
sesquistearate, sorbitan tri-isostearate, sorbitan trioleate,
sorbitan tristearate and mixtures thereof.
89. The method of claim 57, wherein the first composition comprises
a mixture of one or more of hydrophilic and hydrophobic
carriers.
90. The method of claim 57, wherein the second composition
comprises one or more therapeutically active or prophylactic
substances.
91. The method of claim 57, wherein the first composition further
comprises one or more pharmaceutically acceptable excipients.
92. The method of claim 91, wherein the pharmaceutically acceptable
excipient is selected from the group consisting of fillers,
binders, disintegrants, glidants, coloring agents, taste-masking
agents, pH-adjusting agents, solubilizing agents, stabilizing
agents, wetting agents, surface active agents, and
antioxidants.
93. The method of claim 57, wherein the second composition
comprises one or more pharmaceutically acceptable excipients.
94. The method of claim 93, wherein the pharmaceutically acceptable
excipient is one or more of fillers, binders, disintegrants,
glidants, coloring agents, taste-masking agents, pH-adjusting
agents, solubilizing agents, stabilizing agents, wetting agents,
surface active agents, and antioxidants.
95. The method of claim 57, wherein the first or the second
composition comprises a one or more of a cosmetically active
substance, a beneficial substance, a food substance, or a nutrient
substance.
96. The method of claim 57, wherein the second composition
comprises magnesium aluminosilicate or magnesium
aluminometasilicate and the amount of carrier in the particulate
material is at least about 30% v/v.
97. The method of claim 96, wherein the amount of carrier in the
particulate material is at least about 40% v/v.
98. The method of claim 96, wherein the amount of carrier in the
particulate material is at least about 50% v/v.
99. The method of claim 57, wherein the particulate material is
suitable for use in the preparation of tablets.
100. A method for improving the bioavailability of a
therapeutically or prophylactically active substance, comprising:
i) spraying a first composition comprising a therapeutically or
prophylactically active substance, a carrier in liquid form,
wherein the carrier has a melting point of about 5.degree. C. or
more, on a second composition comprising a material in solid form,
the second composition having a temperature corresponding to or
below the melting point temperature of the first composition, and
ii) agglomerating the composition by mixing the second composition
onto which the first composition is sprayed to obtain a particulate
material, wherein either the first or second substance comprises an
aqueous substance with a solubility at 25.degree. C. and pH of 7.4
of at most about 3 mg/ml.
101. A method for improving the shelf-life of a pharmaceutical
composition comprising an oxidation-sensitive therapeutically
active and/or prophylactic substance, comprising subjecting the
substance, before or during manufacture of the pharmaceutical
composition, to the method of claim 100, by incorporating the
substance in the first and the second composition.
102. A particulate material for use in a pharmaceutical, cosmetic,
obtained by the method of claim 100.
103. The particulate material according to claim 102, wherein the
pharmaceutical use is for use in the preparation of a solid dosage
form.
104. The particulate material according to claim 102, wherein the
pharmaceutical use is for use in the preparation of tablets.
105. The particulate material of claim 102, further comprising a
coating selected from one or more of film coatings, modified
release coatings, enteric coatings, protective coatings and
anti-adhesive coatings.
106. The particulate material of claim 105, where the tablets are
obtained by direct compression.
107. A pharmaceutical composition comprising a particulate material
obtained by a method comprising: i) spraying a first composition
comprising a therapeutically or prophylactically active substance
and a carrier in liquid form, wherein the carrier has a melting
point of about 5.degree. C. or more, on a second composition
comprising material in solid form, the second composition having a
temperature corresponding to or below the melting point temperature
of the first composition, and ii) agglomerating the composition by
mixing the second composition onto which the first composition is
sprayed to obtain a particulate material.
108. The pharmaceutical composition of claim 107, wherein the
pharmaceutical composition is in the form of a fluid, semi-solid,
or solid composition.
109. The pharmaceutical composition of claim 107, wherein the
pharmaceutical composition is in the form of a powder, a tablet, a
capsule or a sachet.
110. The pharmaceutical composition of claim 107, wherein the
pharmaceutical composition is in liquid form.
111. The pharmaceutical composition of claim 110, wherein the
liquid form is one or more of a solution, a dispersion, an emulsion
or a suspension.
112. A pharmaceutical particulate material obtained by a process
comprising i) spraying a first composition comprising a
therapeutically or prophylactically active substance and a carrier
in liquid form, wherein the carrier has a melting point of about
5.degree. C. or more, on a second composition comprising a finely
dispersed solid material, the second composition having a
temperature corresponding to or below the melting point temperature
of the first composition, ii) mixing the second composition onto
which the first composition is sprayed to obtain the particles, and
iii) heating the mixture to a temperature that is below the melting
point of the carrier contained in the first composition to form
particulate material having a geometric weight mean diameter of at
least 10 micrometer, wherein a concentration of the carrier in the
particulate material is at least about 40% v/v.
113. The pharmaceutical particulate material of claim 112, wherein
the geometric weight mean diameter is from between about 20 to
about 2000 micrometers.
114. The pharmaceutical particulate material of claim 112, wherein
the particulate material is suitable for use in the preparation of
solid dosage form.
115. The pharmaceutical particulate material of claim 113, wherein
the particulate material is suitable for use in the preparation of
tablets.
116. The pharmaceutical particulate material of claim 114, wherein
the particulate material has sufficient properties with respect to
flowability and/or anti-adhesion so that addition of a lubricant
can be omitted when preparing a solid dosage form.
117. The pharmaceutical particulate material of claim 112, wherein
the first composition further comprises magnesium aluminosilicate
and/or magnesium aluminometasilicate.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the
preparation of a particulate material by a controlled agglomeration
method, i.e. a method that enables a controlled growth in particle
size. The method is especially suitable for use in the preparation
of pharmaceutical compositions containing a therapeutically and/or
prophylactically active substance which has a relatively low
aqueous solubility and/or which is subject to chemical
decomposition. By employment of the novel process, compositions can
be prepared that have improved properties with respect to release
of the active substance from the composition as evidenced by in
vitro dissolution test and/or with respect to improved shelf life
of the compositions upon storage.
[0002] The invention also relates to a particulate material
obtained by the novel process and to pharmaceutical compositions
containing such particulate material. The particulate material
obtained exhibits excellent flowability and compactability and
possess excellent tabletting properties.
BACKGROUND OF THE INVENTION
[0003] There is a need for developing new and improved methods
which enable preparation of pharmaceutical compositions for oral
use that release the active substance from the composition in a
suitable manner to enable an absorption of the active substance
into the circulatory system.
DETAILED DISCLOSURE OF THE INVENTION
[0004] The present invention provides a method for controlled
agglomeration, i.e. a controlled growth in particle size of a
particulate material. Controlled agglomeration is provided using a
process for the preparation of a particulate material (see
below).
[0005] The invention also provides a process for the preparation of
a particulate material, the process comprising [0006] i) spraying a
first composition comprising a carrier, which has a melting point
of about 5.degree. C. or more such as, e.g., about 10.degree. C. or
more, about 20.degree. C. or more or about 25.degree. C. or more
and which is present in the first composition in liquid form, on a
second composition comprising a material in solid form, the second
composition having a temperature of at the most a temperature
corresponding to the melting point of the carrier and/or of the
carrier composition such as, e.g., a temperature of at least about
2.degree. C., at least about 5.degree. C. or at least about
10.degree. C. lower than the melting point of the carrier and/or of
the carrier composition, and [0007] ii) mixing or other means of
mechanical working the second composition onto which the first
composition is sprayed to obtain the particulate material.
[0008] The process enables incorporation in a solid material of a
high load of a carrier of a type that e.g. due to its solubility
properties enables a high load of therapeutically and/or
prophylactically active substances with a relatively low aqueous
solubility. The carrier is normally solid or semi-solid and
normally it has a sticky, oily or waxy character. However, the
carrier may also be fluid at room temperature or even at
temperature below 5.degree. C. and in such cases it is contemplated
that the process is carried out by employment of cooling of the
second composition. By employment of the novel controlled
agglomeration method a particulate material with a high load of
carrier may be prepared and the resulting particulate material
appears as a particulate powder in solid form. The particulate
material obtained by the novel method has excellent properties with
respect to flowability, bulk density, compactability and thus, it
is suitable for use in the preparation of e.g. tablets. Although
the particulate material may have a high load of a carrier of
substantially sticky character the particulate material prepared
has minimal, if any, adherence to tablet punches and/or dies during
manufacture of tablets.
[0009] Methods for the preparation of granular products are
described e.g. in EP-A-0 306 465 (Lejus Medical Aktiebolag), JP
60184378 (Takeda) and in WO 01/22941 (H. Lundbeck A/S). However, in
none of these documents is described a method for the preparation
of a particulate material, which method enables incorporation of a
relatively high amount of a carrier as defined below and at the
same time controlling the size of the particles obtained.
Carriers and Carrier Compositions
[0010] As indicated above an important step in the process for the
preparation of a particulate material according to the invention is
the addition of a carrier or a carrier composition. The carrier is
of a type, which has a melting point of at least about 25.degree.
C. such as, e.g., at least about 30.degree. C. at least about
35.degree. C. or at least about 40.degree. C. For practical
reasons, the melting point may not be too high, thus, the carrier
normally has a melting point of at the most about 300.degree. C.
such as, e.g., at the most about 250.degree. C., at the most about
200.degree. C., at the most about 150.degree. C. or at the most
about 100.degree. C. If the melting point is higher then it becomes
very difficult to ensure maintenance of a sufficient high
temperature during the delivery of the carrier to the spraying
equipment necessary to provide the melted carrier (or carrier
composition) in the form of a spray. Furthermore, in those cases
where e.g. a therapeutically and/or prophylactically active
substance is included in the carrier composition, a relatively high
temperature may promote e.g. oxidation or other kind of degradation
of the substance.
[0011] In the present context, the melting point is determined by
DSC (Differential Scanning Calorimetry). The melting point is
determined as the temperature at which the linear increase of the
DSC curve intersect the temperature axis (see FIG. 8 for further
details).
[0012] Suitable carriers are generally substances, which are used
in the manufacture of pharmaceuticals as so-called melt binders or
solid solvents (in the form of solid dosage form), or as
co-solvents or ingredients in pharmaceuticals for topical use.
[0013] The carrier may be hydrophilic, hydrophobic and/or they may
have surface-active properties. In general hydrophilic and/or
hydrophobic carriers are suitable for use in the manufacture of a
pharmaceutical composition comprising a therapeutically and/or
prophylactically active substance that has a relatively low aqueous
solubility and/or when the release of the active substance from the
pharmaceutical composition is designed to be immediate or
non-modified. Hydrophobic carriers, on the other hand, are normally
used in the manufacture of a modified release pharmaceutical
composition. The above-given considerations are simplified to
illustrate general principles, but there are many cases where other
combinations of carriers and other purposes are relevant and,
therefore, the examples above should not in any way limit the
invention.
[0014] Examples on a suitable carrier are a hydrophilic carrier, a
hydrophobic carrier, a surfactant or mixtures thereof.
[0015] Typically, a suitable hydrophilic carrier is selected from
the group consisting of: polyether glycols such as, e.g.,
polyethylene glycols, polypropylene glycols; polyoxyethylenes;
polyoxypropylenes; poloxamers and mixtures thereof, or it may be
selected from the group consisting of: xylitol, sorbitol, potassium
sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol,
behenic acid, hydroquinon monomethyl ether, sodium acetate, ethyl
fumarate, myristic acid, citric acid, Gelucire 50/13, other
Gelucire types such as, e.g., Gelucire 44/14 etc., Gelucire 50/10,
Gelucire 62/05, Sucro-ester 7, Sucro-ester 11, Sucro-ester 15,
maltose, mannitol and mixtures thereof.
[0016] A hydrophobic carrier for use in a process of the invention
may be selected from the group consisting of: straight chain
saturated hydrocarbons, sorbitan esters, paraffins; fats and oils
such as e.g., cacao butter, beef tallow, lard, polyether glycol
esters; higher fatty acid such as, e.g. stearic acid, myristic
acid, palmitic acid, higher alcohols such as, e.g., cetanol,
stearyl alcohol, low melting point waxes such as, e.g., glyceryl
monostearate, hydrogenated tallow, myristyl alcohol, stearyl
alcohol, substituted and/or unsubstituted monoglycerides,
substituted and/or unsubstituted diglycerides, substituted and/or
unsubstituted triglycerides, yellow beeswax, white beeswax,
carnauba wax, castor wax, japan wax, acetylate monoglycerides; NVP
polymers, PVP polymers, acrylic polymers, or a mixture thereof.
[0017] In an interesting embodiment, the carrier is a polyethylene
glycol having an average molecular weight in a range of from about
400 to about 35,000 such as, e.g., from about 800 to about 35,000,
from about 1,000 to about 35,000 such as, e.g., polyethylene glycol
1,000, polyethylene glycol 2,000, polyethylene glycol 3,000,
polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene
glycol 6000, polyethylene glycol 7,000, polyethylene glycol 8,000,
polyethylene glycol 9,000 polyethylene glycol 10,000, polyethylene
glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol
35,000. In certain situations polyethylene glycol may be employed
with a molecular weight from about 35,000 to about 100,000.
[0018] In another interesting embodiment, the carrier is
polyethylene oxide having a molecular weight of from about 2,000 to
about 7,000,000 such as, e.g. from about 2,000 to about 100,000,
from about 5,000 to about 75,000, from about 10,000 to about
60,000, from about 15,000 to about 50,000, from about 20,000 to
about 40,000, from about 100,000 to about 7,000,000 such as, e.g.,
from about 100,000 to about 1,000,000, from about 100,000 to about
600,000, from about 100,000 to about 400,000 or from about 100,000
to about 300,000.
[0019] In another embodiment, the carrier is a poloxamer such as,
e.g. Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407
or other block copolymers of ethylene oxide and propylene oxide
such as the Pluronic.RTM. and/or Tetronic.RTM. series. Suitable
block copolymers of the Pluronic.RTM. series include polymers
having a molecular weight of about 3,000 or more such as, e.g. from
about 4,000 to about 20,000 and/or a viscosity (Brookfield) from
about 200 to about 4,000 cps such as, e.g., from about 250 to about
3,000 cps. Suitable examples include Pluronic.RTM. F38, P65, P68LF,
P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123,
F123, F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable block copolymers
of the Tetronic.RTM. series include polymers having a molecular
weight of about 8,000 or more such as, e.g., from about 9,000 to
about 35,000 and/or a viscosity (Brookfield) of from about 500 to
about 45,000 cps such as, e.g., from about 600 to about 40,000. The
viscosities given above are determined at 60.degree. C. for
substances that are pastes at room temperature and at 77.degree. C.
for substances that are solids at room temperature.
[0020] The carrier may also be a sorbitan ester such as, e.g.,
sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate,
sorbitan monoisostearate, sorbitan monooleate, sorbitan
monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate,
sorbitan sesquioleate, sorbitan sesquistearate, sorbitan
tri-isostearate, sorbitan trioleate, sorbitan tristearate or
mixtures thereof.
[0021] The carrier composition may of course comprise a mixture of
different carriers such as, e.g., a mixture of hydrophilic and/or
hydrophobic carriers.
[0022] In another interesting embodiment, the carrier is a
surfactant or a substance having surface-active properties. It is
contemplated that such substances are involved in the wetting of
e.g. slightly soluble active substance and thus, contributes to
improved solubility characteristics of the active substance.
[0023] Examples on surfactants are given in the following. In order
to be suitable for use as a carrier, the criteria with respect to
melting point and/or viscosity discussed herein must be fulfilled.
However, the list below encompasses surfactants in general, because
surfactants may also be added to the carrier composition in the
form of pharmaceutically acceptable excipients.
[0024] In a process according to the invention, the carrier may be
employed as such or in the form of a carrier composition. A carrier
composition comprises one or more carriers optionally together with
one or more other ingredients. Thus, the carrier composition may
comprise a mixture of hydrophilic and/or hydrophobic carriers
and/or surfactants. The carrier composition may also comprise one
or more therapeutically and/or prophylactically active substances
and/or one or more pharmaceutically acceptable excipients.
[0025] Suitable excipients for use in a carrier composition
(and--as discussed above--for use as carriers it selves) are
surfactants such as, e.g., hydrophobic and/or hydrophilic
surfactants as those disclosed in WO 00/50007 in the name of
Lipocine, Inc. Examples on suitable surfactants are [0026] i)
polyethoxylated fatty acids such as, e.g. fatty acid mono- or
diesters of polyethylene glycol or mixtures thereof such as, e.g.
mono--or diesters of polyethylene glycol with lauric acid, oleic
acid, stearic acid, myristic acid, ricinoleic acid, and the
polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG
7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30,
PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400,
PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000,
PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG
15,000, PEG 20,000, PEG 35,000, [0027] ii) polyethylene glycol
glycerol fatty acid esters, i.e. esters like the above-mentioned
but in the form of glyceryl esters of the individual fatty acids;
[0028] iii) glycerol, propylene glycol, ethylene glycol, PEG or
sorbitol esters with e.g. vegetable oils like e.g. hydrogenated
castor oil, almond oil, palm kernel oil, castor oil, apricot kernel
oil, olive oil, peanut oil, hydrogenated palm kernel oil and the
like, [0029] iv) polyglycerized fatty acids like e.g. polyglycerol
stearate, polyglycerol oleate, polyglycerol ricinoleate,
polyglycerol linoleate, [0030] v) propylene glycol fatty acid
esters such as, e.g. propylene glycol monolaurate, propylene glycol
ricinoleate and the like, [0031] vi) mono- and diglycerides like
e.g. glyceryl monooleate, glyceryl dioleae, glyceryl mono- and/or
dioleate, glyceryl caprylate, glyceryl caprate etc.; [0032] vii)
sterol and sterol derivatives; [0033] viii) polyethylene glycol
sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as
esters of PEG with the various molecular weights indicated above,
and the various Tween.RTM. series; [0034] ix) polyethylene glycol
alkyl ethers such as, e.g. PEG oleyl ether and PEG lauryl ether;
[0035] x) sugar esters like e.g. sucrose monopalmitate and sucrose
monolaurate; [0036] xi) polyethylene glycol alkyl phenols like e.g.
the Triton.RTM. X or N series; [0037] xii)
polyoxyethylene-polyoxypropylene block copolymers such as, e.g.,
the Pluronic.RTM. series, the Synperonic.RTM. series, Emkalyx.RTM.,
Lutrol.RTM., Supronic.RTM. etc. The generic term for these polymers
is "poloxamers" and relevant examples in the present context are
Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188,
212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333,
334, 335, 338, 401, 402, 403 and 407; [0038] xiii) sorbitan fatty
acid esters like the Span.RTM. series or Ariacel.RTM. series such
as, e.g. sorbinan monolaurate, sorbitan monopalmitate, sorbitan
monooleate, sorbitan monostearate etc.; xiv) lower alcohol fatty
acid esters like e.g. oleate, isopropyl myristate, isopropyl
palmitate etc.; [0039] xiv) ionic surfactants including cationic,
anionic and zwitterionic surfactants such as, e.g. fatty acid
salts, bile salts, phospholipids, phosphoric acid esters,
carboxylates, sulfates and sulfonates etc.
[0040] When a surfactant or a mixture of surfactants is present in
a carrier composition the concentration of the surfactant(s) is
normally in a range of from about 0.1-75% w/w such as, e.g., from
about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from
about 0.5 to about 10% w/w, or alternatively, when applicable as a
carrier or a part of the carrier composition from about 20 to about
75% w/w such as, e.g. from about 25 to about 70% w/w, from about 30
to about 60% w/w.
[0041] Other suitable excipients in a carrier composition may be
solvents or semi-solid excipients like, e.g. propylene glycol,
polyglycolised glycerides including Gelucire 44/14, complex fatty
materials of plant origin including theobroma oil, carnauba wax,
vegetable oils like e.g. almond oil, coconut oil, corn oil,
cottonseed oil, sesame oil, soya oil, olive oil, castor oil, palm
kernels oil, peanut oil, rape oil, grape seed oil etc.,
hydrogenated vegetable oils such as, e.g. hydrogenated peanut oil,
hydrogenated palm kernels oil, hydrogenated cottonseed oil,
hydrogenated soya oil, hydrogenated castor oil, hydrogenated
coconut oil; natural fatty materials of animal origin including
beeswax, lanolin, fatty alcohols including cetyl, stearyl, lauric,
myristic, palmitic, stearic fatty alcohols; esters including
glycerol stearate, glycol stearate, ethyl oleate, isopropyl
myristate; liquid interesterified semi-synthetic glycerides
including Miglycol 810/812; amide or fatty acid alcolamides
including stearamide ethanol, diethanolamide of fatty coconut acids
etc.
[0042] Other additives in the carrier composition may be
antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,
monothioglycerol, potassium metabisulfite, propyl gallate, sodium
formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate,
sulfur dioxide, tocopherol, tocopherol acetate, tocopherol
hemisuccinate, TPGS or other tocopherol derivatives, etc. The
carrier composition may also contain e.g. stabilising agents. The
concentration of an antioxidant and/or a stabilizing agent in the
carrier composition is normally from about 0.1% w/w to about 5%
w/w.
[0043] In those cases where a carrier composition is employed, the
requirements with respect to the melting point mentioned above
normally also apply to the carrier composition, especially in those
cases where a minor amount of water is included in the carrier
composition. However, when the carrier composition is heated the
carrier composition may be in the form of two or more phases (e.g.
two distinct liquid phase, or a liquid phase comprising e.g. an
active substance dispersed therein). In such cases, the melting
point is not a true melting point but merely a heating point where
the carrier composition becomes in a liquid form, which is suitable
for use in a spraying device. Often such a heating point will for
practical purposes correspond to the melting point of the carrier
itself.
[0044] The total concentration of carrier(s) in the carrier
composition is normally in a range of from about 5 to about 100%
w/w such as, e.g., from about 10 to about 99.5% w/w, from about 15
to about 99% w/w, from about 15 to about 98% w/w, from about 15 to
about 97% w/w, from about 20 to about 95% w/w such as at least
about 25% w/w, at least about 30% w/w, at least about 35% w/w, at
least about 40% w/w, at least about 45% w/w, at least about 50%
w/w, at least about 55% w/w, at least about 60% w/w, at least about
65% w/w, at least about 70% w/w, at least about 75% w/w, at least
about 80% w/w, at least about 85% w/w, at least about 90% w/w, at
least about 95% w/w or at least about 98% w/w.
[0045] As explained above, in a process according to the invention
the carrier or the carrier composition is brought on liquid form by
heating the carrier and/or the carrier composition to a
temperature, which causes the carrier and/or the carrier
composition to melt, and the carrier in liquid form (i.e. as a
solution or a dispersion) is sprayed on the second composition.
[0046] As mentioned above, the carrier or the carrier composition
in melted or liquidized form is sprayed on a second composition.
Thus, the carrier or the carrier composition should have a suitable
viscosity. If the viscosity is too high, the carrier or carrier
composition will be too "thick" and will have a tendency of
adhering to the nozzle, which may result in that the delivery
through the nozzle is stopped. For the present purpose a viscosity
of the carrier and/or the carrier composition is suitably if the
viscosity (Brookfield DV-III) is at the most about 800 mPas at a
temperature of at the most 100.degree. C. such as, e.g., at the
most 700, at the most 600, at the most 500 mPas. In those cases
where the melting point of the carrier or the carrier composition
is more than about 80.degree. C., the viscosity values mentioned
above are at a temperature of about 40.degree. C. above the melting
point.
[0047] In the particulate material obtained by a process according
to the invention, the concentration of the carrier is from about 5
to about 95% w/w such as, e.g. from about 5 to about 90% w/w, from
about 5 to about 85% w/w, from about 5 to about 80% w/w, from about
10 to about 75% w/w, from about 15 to about 75% w/w, from about 20
to abut 75% w/w, from about 25% to about 75% w/w, from about 30% to
about 75% w/w. from about 35% to about 75% w/w, from about 25% to
about 70% w/w, from about 30% to about 70% w/w, from about 35% to
abut 70% w/w. from about 40% to about 70% w/w, from about 45% to
about 65% w/w or from about 45% to about 60% w/w.
[0048] In those cases where the second composition comprises a
pharmaceutically acceptable excipient that has a relatively high
particle density it is preferred that the concentration of the
carrier in the particulate material obtained by a process of the
invention is from about 5 to about 95% v/v such as, e.g. from about
5 to about 90% v/v, from about 5 to about 85% v/v, from about 5 to
about 80% v/v, from about 10 to about 75% v/v from about 15 to
about 75% v/v, from about 20 to abut 75% v/v, from about 25% to
about 75% v/v, from about 30% to about 75% v/v, from about 35% to
about 75% v/v, from about 25% to about 70% v/v, from about 30% to
about 70% v/v, from about 35% to abut 70% v/v, from about 40% to
about 70% v/v, from about 45% to about 65% v/v or from about 45% to
about 60% v/v.
[0049] In the following is given a calculation example:
[0050] Recalculation from % w/w to % v/v (of total
composition):
Particle density of lactose: 1.56 g/cm.sup.3
Particle density of calcium hydrogen phosphate anhydrous: 2.89
g/cm.sup.3
Particle density of PEG 6000: 1.17 g/cm.sup.3
[0051] For lactose: w/w ratio of 50% PEG 6000/(lactose+PEG 6000)
equals a % v/v of 56% For calcium hydrogen phosphate anhydrous: w/w
ratio of 50% PEG 6000/(calcium hydrogen phosphate anhydrous+PEG
6000) equals a % v/v of 71%.
[0052] In many cases it is suitable to dissolve or disperse a
therapeutically and/or prophylactically active substance in the
carrier or in the carrier composition. Suitable therapeutically
and/or prophylactically active substances are discussed below.
[0053] In a process according to the invention it is not necessary
to employ water or an aqueous medium e.g. together with a binder in
order to build up agglomerates of a suitable size. The
agglomeration suitably takes place under water-free or
substantially water-free conditions. Thus, the process is also very
useful when active substances or other ingredients are employed
which are susceptible to water (e.g. degradation under aqueous
conditions). However, if desired, water or an aqueous medium may of
course be incorporated in the carrier composition. Although the
carrier composition normally is essentially non-aqueous, water may
be present to a certain extent and then the concentration of water
in the carrier composition is the most about 20% w/w water such as
at the most about 15% w/w, at the most abut 10% w/w, at the most
about 5% w/w or at the most about 2.5% w/w.
Therapeutically and/or Prophylactically Active Substances
[0054] In a preferred embodiment of the invention the particulate
material obtained by a process according to the invention comprises
a therapeutically and/or prophylactically active substance. The
particulate matter may also or alternatively comprise a
cosmetically active substance (i.e. a substance that is employed in
cosmetic compositions). In a process according to the invention the
active substance may be included in the carrier composition and/or
in the second composition.
[0055] In the present context a therapeutically and/or
prophylactically active substance includes any biologically and/or
physiologically active substance that has a function on an animal
such as, e.g. a mammal like a human. The term includes drug
substances, hormones, genes or gene sequences, antigen- comprising
material, proteins, peptides, nutrients like e.g. vitamins,
minerals, lipids and carbohydrates and mixtures thereof. Thus, the
term includes substances that have utility in the treatment and/or
preventing of diseases or disorders affecting animals or humans, or
in the regulation of any animal or human physiological condition.
The term also includes any biologically active substance which,
when administered in an effective amount, has an effect on living
cells or organisms.
[0056] Many active substances have and it is expected that many of
the future drug substances will have undesired properties
especially with respect to water solubility and to oral
bioavailability. Therefore, a novel technology, which enables
especially therapeutically and/or prophylactically active
substances to be delivered to the body in a relatively easy manner
and at the same time enables the desired therapeutic and/or
prophylactic response, is highly needed.
[0057] By employment of a process according to the present
invention it is contemplated that this object can be achieved for
many such substances, especially in view of the promising results
the inventors have obtained from a study in Beagle dogs.
Accordingly, the present inventors have found very promising
results with respect to bioavailability when a process according to
the invention is employed for the preparation of particulate
material containing an active substance with a very low aqueous
solubility. Thus, a process according to the invention is
especially suitable for use for the preparation of particulate
material comprising an active substance that has an aqueous
solubility at 25.degree. C. and pH of 7.4 of at the most about 3
mg/ml such as, e.g., at the most about 2 mg/ml, at the most about 1
mg/ml, at the most about 750 .mu.g/ml, at the most about 500
.mu.g/ml, at the most about 250 .mu.g/ml; at the most about 100
.mu.g/ml, at the most about 50 .mu.g/ml, at the most about 25
.mu.g/ml, at the most about 20 .mu.g/ml or at the most about 10
.mu.g/ml. In specific embodiments the solubility of the active
substance may be much lower such as, e.g., at the most about 1
.mu.g/ml, at the most about 100 ng/ml, at the most about 75 ng/ml
such as about 50 ng/ml.
[0058] As mentioned above, a process according to the invention may
advantageously be carried out without employment of water or an
aqueous medium. Thus, the process is especially suitable for use
for active substances that are degraded, decomposed or otherwise
influenced by water.
[0059] Examples on active substances suitable for use in a
particulate material according to the invention are in principle
any active substance such as, e.g. freely water soluble as well as
more slightly or insoluble active substances. Thus, examples on
active substances suitable for use are e.g. antibacterial
substances, antihistamines and decongestants, anti-inflammatory
agents, antiparasitics, antivirals, local anesthetics, antifungals,
amoebicidals or trichomonocidal agents, analgesics, antianxiety
agents, anticlotting agents, antiarthritics, antiasthmatics,
antiarthritic, anticoagulants, anticonvulsants, antidepressants,
antidiabetics, antiglaucoma agents, antimalarials, antimicrobials,
antineoplastics, antiobesity agents, antipsychotics,
antihypertensives, antitussives, auto-immune disorder agents,
anti-impotence agents, anti-Parkinsonism agents, anti-Alzheimers'
agents, antipyretics, anticholinergics, anti-ulcer agents,
anorexic, beta-blockers, beta-2 agonists, beta agonists, blood
glucose-lowering agents, bronchodilators, agents with effect on the
central nervous system, cardiovascular agents, cognitive enhancers,
contraceptives, cholesterol-reducing agents, cytostatics,
diuretics, germicidals, H-2 blockers, hormonal agents, hypnotic
agents, inotropics, muscle relaxants, muscle contractants, physic
energizers, sedatives, sympathomimetics, vasodilators,
vasoconstrictors, tranquilizers, electrolyte supplements, vitamins,
counterirritants, stimulants, anti-hormones, drug antagonists,
lipid-regulating agents, uricosurics, cardiac glycosides,
expectorants, purgatives, contrast materials, radiopharmaceuticals,
imaging agents, peptides, enzymes, growth factors, etc.
[0060] Specific examples include e.g.
[0061] Anti-inflammatory drugs like e.g. ibuprofen, indometacin,
naproxen, nalophine;
[0062] Anti-Parkinsonism agents like e.g. bromocriptine, biperidin,
benzhexol, benztropine etc.
[0063] Antidepressants like e.g. imipramine, nortriptyline,
pritiptyline, etc.
[0064] Antibiotics like e.g. clindamycin, erythomycin, fusidic
acid, gentamicin, mupirocine, amfomycin, neomycin, metronidazol,
sulphamethizole, bacitracin, framycetin, polymyxin B, acitromycin
etc,
[0065] Antifungal agents like e.g. miconazol, ketoconaxole,
clotrimazole, amphotericin B, nystatin, mepyramin, econazol,
fluconazol, flucytocine, griseofulvin, bifonazole, amorofine,
mycostatin, itrconazole, terbenafine, terconazole, tolnaftate
etc.
[0066] Antimicrobial agents like e.g. metronidazole, tetracyclines,
oxytetracylines, penicillins etc.
[0067] Antiemetics like e.g. metoclopramide, droperidol,
haloperidol, promethazine etc.
[0068] Antihistamines like e.g. chlorpheniramine, terfenadine,
triprolidine etc.
[0069] Antimigraine agents like e.g. dihydroergotamine, ergotamine,
pizofylline etc.
[0070] Coronary, cerebral or peripheral vasodilators like e.g.
nifedipine, diltiazem etc.
[0071] Antianginals such as, e.g., glyceryl nitrate, isosorbide
dinitrate, molsidomine, verapamil etc.
[0072] Calcium channel blockers like e.g. verapamil, nifedipine,
diltiazem, nicardipine etc.
[0073] Hormonal agents like e.g. estradiol, estron, estriol,
polyestradiol, polyestriol, dienestrol, diethylstilbestrol,
progesterone, dihydroprogesterone, cyprosterone, danazol,
testosterone etc.
[0074] Contraceptive agents like e.g. ethinyl estradiol,
lynestrenol, etynodiol, norethisterone, mestranol, norgestrel,
levonorgestrel, desodestrel, medroxyprogesterone etc.
[0075] Antithrombotic agents like e.g. heparin, warfarin etc.
[0076] Diuretics like e.g. hydrochlorothiazide, flunarizine,
minoxidil etc.
[0077] Antihypertensive agents like e.g. propanolol, metoprolol,
clonidine, pindolol etc.
[0078] Corticosteroids like e.g. beclomethasone, betamethasone,
betamethasone-17-valerate, betamethasone-dipropionate, clobetasol,
clobetasol-17-butyrate, clobetasol-propionate, desonide,
desoxymethasone, dexamethasone, diflucortolone, flumethasone,
flumethasone-pivalte, fluocinolone acetonide, fluocinoide;
hydrocortisone, hydrocortisone-17-butyrate,
hydrocortisonebuteprate, methylprednisolone, triamcinolone
acetonide, hacinonide, fluprednide acetate,
alklometasone-dipropionate, fluocortolone, fluticason-propionte,
mometasone-furate, desoxymethasone, diflurason-diacetate,
halquinol, cliochinol, chlorchinaldol, fluocinolone-acetonide
etc.
[0079] Dermatological agents like e.g. nitrofurantoin, dithranol,
clioquinol, hydroxyquinoline, isotretionin, methoxsalen,
methotrexate, tretionin, trioxalen, salicylic acid, penicillamine
etc.
[0080] Steroids like e.g. estradiol, progesterone, norethindrone,
levonorgestrel, ethynodiol, levonorgestrol, norgestimate, gestanin,
desogestrel, 3-keton-desogesterel, demegestone, promethoestrol,
testosterone, spironolactone and esters thereof etc.
[0081] Nitro compounds like e.g. amyl nitrates, nitroglycerine and
isosorbide nitrate etc.
[0082] Opioids like e.g. morphine, buprenorphine, oxymorphone,
hydromorphone, codeine, tramadol etc.
[0083] Prostaglandins such as, e.g., a member of the PGA, PGB, PGE
or PGF series such as, e.g. minoprostol, dinoproston, carboprost,
eneprostil etc.
[0084] Peptides like e.g. growth hormone releasing factors, growth
factors (e.g. epidermal growth factor (EGF), nerve growth factor
(NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth
factor (aFGF, bFGF etc.), somatostatin, calcitonin, insulin,
vasopressin, interferons, IL-2 etc., urokinase, serratiopeptidase,
superoxide dismutase, thyrotropin releasing hormone, lutenizing
hormone releasing hormone (LH-RH), corticotrophin releasing
hormone, growth hormone releasing hormone (GHRH), oxytocin,
erythropoietin (EPO), colony stimulating factor (CSF) etc.
[0085] Interesting examples on active substances that are slightly
soluble, sparingly soluble or insoluble in water are given in the
following tables: TABLE-US-00001 TABLE 1 Poorly-Soluble Drug
Candidates Drug Name Therapeutic Class Solubility In Water
Alprazolam CNS Insoluble Amiodarone Cardiovascular Very Slightly
Amlodipine Cardiovascular Slightly Astemizole Respiratory Insoluble
Atenolol Cardiovascular Slightly Azathioprine Anticancer Insoluble
Azelastine Respiratory Insoluble Beclomethasone Respiratory
Insoluble Budesonide Respiratory Sparingly Buprenorphine CNS
Slightly Butalbital CNS Insoluble Carbamazepine CNS Insoluble
Carbidopa CNS Slightly Cefotaxime Anti-infective Sparingly
Cephalexin Anti-infective Slightly Cholestyramine Cardiovascular
Insoluble Ciprofloxacin Anti-infective Insoluble Cisapride
Gastrointestinal Insoluble Cisplatin Anticancer Slightly
Clarithromycin Anti-infective Insoluble Clonazepam CNS Slightly
Clozapine CNS Slightly Cyclosporin Immunosuppressant Practically
Insoluble Diazepam CNS Slightly Diclofenac sodium NSAID Sparingly
Digoxin Cardiovascular Insoluble Dipyridamole Cardiovascular
Slightly Divalproex CNS Slightly Dobutamine Cardiovascular
Sparingly Doxazosin Cardiovascular Slightly Enalapril
Cardiovascular Sparingly Estradiol Hormone Insoluble Etodolac NSAID
Insoluble Etoposide Anticancer Very Slightly Famotidine
Gastrointestinal Slightly Felodipine Cardiovascular Insoluble
Fentanyl citrate CNS Sparingly Fexofenadine Respiratory Slightly
Finasteride Genito-urinary Insoluble Fluconazole Antifungal
Slightly Flunosolide Respiratory Insoluble Flurbiprofen NSAID
Slightly Fluvoxamine CNS Sparingly Furosemide Cardiovascular
Insoluble Glipizide Metabolic Insoluble Glyburide Metabolic
Sparingly Ibuprofen NSAID Insoluble Isosorbide dinitrate
Cardiovascular Sparingly Isotretinoin Dermatological Insoluble
Isradipine Cardiovascular Insoluble Itraconzole Antifungal
Insoluble Ketoconazole Antifungal Insoluble Ketoprofen NSAID
Slightly Lamotrigine CNS Slightly Lansoprazole Gastrointestinal
Insoluble Loperamide Gastrointestinal Slightly Loratadine
Respiratory Insoluble Lorazepam CNS Insoluble Lovastatin
Cardiovascular Insoluble Medroxyprogesterone Hormone Insoluble
Mefenamic acid Analgesic Slightly Methylprednisolone Steroid
Insoluble Midazolam Anesthesia Insoluble Mometasone Steroid
Insoluble Nabumetone NSAID Insoluble Naproxen NSAID Insoluble
Nicergoline CNS Insoluble Nifedipine Cardiovascular Practically
Insoluble Norfloxacin Anti-infective Slightly Omeprazole
Gastrointestinal Slightly Paclitaxel Anticancer Insoluble Phenytoin
CNS Insoluble Piroxicam NSAID Sparingly Quinapril Cardiovascular
Insoluble Ramipril Cardiovascular Insoluble Risperidone CNS
Insoluble Saquinavir Protease inhibitor Practically insoluble
Sertraline CNS Slightly Simvastatin Cardiovascular Insoluble
Terbinafine Antifungal Slightly Terfenadine Respiratory Slightly
Triamcinolone Steroid Insoluble Valproic acid CNS Slightly Zolpidem
CNS Sparingly
[0086] TABLE-US-00002 TABLE 2 Poorly-Soluble Drugs with Low
Bioavailability Drug Name Indication Solubility In Water
Bioavailability Astemizole Allergic Rhinitis Insoluble Low-moderate
Cyclandelate Peripheral vascular disease Insoluble Low Perphenazine
Psychotic disorder Insoluble Low Testosterone Androgen Replacement
Therapy Insoluble Low Famotidine GERD Slightly soluble Low (39-50%)
Budesonide Allergic Rhinitis Sparingly soluble Low (.about.15%)
Mesalamine Irritable Bowel Syndrome Slightly soluble Low
(.about.20%) Clemastine fumarate Allergic Rhinitis Slightly soluble
Low (.about.39%) Buprenorphine Pain Slightly soluble Low (<30%)
Sertraline Anxiety Slightly soluble Low (<44%) Auranofin
Arthritis Slightly soluble Low (15-25%) Felodipine Hypertension
Insoluble Low (15%) Isradipine Hypertension Insoluble Low (15-24%)
Danazol Endometriosis Insoluble Low Loratadine Allergic Rhinitis
Insoluble Low Isosorbide dinitrate Angina Sparingly soluble Low
(20-35%) Fluphenazine Psychotic disorder Insoluble Low (2-3%)
Spironolactone Hypertension, Edema Insoluble Low (25%) Biperiden
Parkinson's disease Sparingly soluble Low (29-33%) Cyclosporin
Transplantation Slightly soluble Low (30%) Norfloxacin Bacterial
Infection Slightly soluble Low (30-40%) Cisapride GERD Insoluble
Low (35-40%) Nabumetone Arthritis Insoluble Low (35%) Dronabinol
ANTIEMETIC Insoluble Low 10-20%) Lovastatin Hyperlipidemia
Insoluble Low (.about.5%) Simvastatin Hyperlipidemia Insoluble Low
(<5%)
[0087] The amount of active substance incorporated in a particulate
material (and/or in a pharmaceutical, cosmetic or food composition)
may be selected according to known principles of pharmaceutical
formulation. In general, the dosage of the active substance present
in a particulate material according to the invention depends inter
alia on the specific drug substance, the age and condition of the
patient and of the disease to be treated.
[0088] A particulate material according to the invention may
comprise a cosmetically active ingredient and/or a food ingredient.
Specific examples include vitamins, minerals, vegetable oils,
hydrogenated vegetable oils, etc.
Second Composition
[0089] As mentioned above the carrier or carrier composition is
sprayed on a second composition. In order to be able to achieve a
high amount of carrier in the final particulate material and in
order to enable a controlled agglomeration of the particles
comprised in the second composition, the present inventors have
surprisingly found that in specific embodiments, the second
composition should initially have a temperature which is at least
about 10.degree. C. such as, e.g., at least about 15.degree. C., at
least about 20.degree. C., at least about 25.degree. C., or at
least about 30.degree. C. below the melting point of the carrier or
carrier composition (or, as discussed above, the heating point of
the carrier composition). However, as mentioned above, a
temperature difference of at least about 10.degree. C. it is not
always necessary. Thus, the second composition may have a
temperature of at the most a temperature corresponding to the
melting point of the carrier and/or of the carrier composition such
as, e.g., a temperature of at least about 2.degree. C., at least
about 5.degree. C. No external heating of the second composition is
normally employed during the process of the invention, but in some
cases it may be advantageous to employ a cooling via the inlet air.
However, the temperature of the second composition may increase to
a minor extent due to the working of the composition. However, the
temperature must (or will) not be higher than at the most the
melting point of the carrier or carrier composition such as, e.g.
at the most about 5.degree. C. such as at the most about 10.degree.
C., at the most about 15.degree. C. or at the most about 20.degree.
C. below the melting point of the carrier or the carrier
composition. Accordingly, a process of the invention can be carried
out without any heating of the second composition, i.e. it can be
carried out at ambient or room temperature (i.e. normally in a
range of from about 20.degree. C. to about 25.degree. C.).
[0090] In contrast thereto, known melt granulation methods involve
external heating of the material that is to be granulated (or
agglomerated) together with a melt binder.
[0091] The second composition comprises pharmaceutically and/or
cosmetically acceptable excipients and, furthermore, a
therapeutically and/or prophylactically active substance may be
present in the second composition.
[0092] In the present context the terms "pharmaceutically
acceptable excipient" and "cosmetically acceptable excipient" are
intended to denote any material, which is inert in the sense that
it substantially does not have any therapeutic and/or prophylactic
effect per se. Such an excipient may be added with the purpose of
making it possible to obtain a pharmaceutical and/or cosmetic
composition, which has acceptable technical properties.
[0093] Examples on suitable excipients for use in a second
composition include fillers, diluents, disintegrants, binders,
lubricants etc. or mixture thereof. As the particulate material
obtained by a process according to the invention may be used for
different purposes, the choice of excipients is normally made taken
such different uses into considerations. Other pharmaceutically
acceptable excipients for use in a second composition (and/or in
the carrier composition) are e.g. acidifying agents, alkalizing
agents, preservatives, antioxidants, buffering agents, chelating
agents, coloring agents, complexing agents, emulsifying and/or
solubilizing agents, flavors and perfumes, humectants, sweetening
agents, wetting agents etc.
[0094] Examples on suitable fillers, diluents and/or binders
include lactose (e.g. spray-dried lactose, .alpha.-lactose,
.beta.-lactose, Tabletose.RTM., various grades of Pharmatose.RTM.,
Microtose.RTM. or Fast-Floc.RTM.), microcrystalline cellulose
(various grades of Avicel.RTM., Elcema.RTM., Vivacel.RTM., Ming
Tai.RTM. or Solka-Floc.RTM.), hydroxypropylcellulose,
L-hydroxypropylcellulose (low substituted), hydroxypropyl
methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of
Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E
and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose
65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and
the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),
methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,
Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium
carboxymethylcellulose, carboxymethylene,
carboxymethylhydroxyethylcellulose and other cellulose derivatives,
sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins,
starches or modified starches (including potato starch, maize
starch and rice starch), calcium phosphate (e.g. basic calcium
phosphate, calcium hydrogen phosphate, dicalcium phosphate
hydrate), calcium sulfate, calcium carbonate, sodium alginate,
collagen etc.
[0095] Specific examples of diluents are e.g. calcium carbonate,
dibasic calcium phosphate, tribasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, powdered cellulose, dextrans,
dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol,
starch, pregelatinized starch, sucrose, sugar etc.
[0096] Specific examples of disintegrants are e.g. alginic acid or
alginates, microcrystalline cellulose, hydroxypropyl cellulose and
other cellulose derivatives, croscarmellose sodium, crospovidone,
polacrillin potassium, sodium starch glycolate, starch,
pregelatinized starch, carboxymethyl starch (e.g. Primogel.RTM. and
Explotab.RTM.) etc.
[0097] Specific examples of binders are e.g. acacia, alginic acid,
agar, calcium carrageenan, sodium carboxymethylcellulose,
microcrystalline cellulose, dextrin, ethylcellulose, gelatin,
liquid glucose, guar gum, hydroxypropyl methylcellulose,
methylcellulose, pectin, PEG, povidone, pregelatinized starch
etc.
[0098] Glidants and lubricants may also be included in the second
composition. Examples include stearic acid, magnesium stearate,
calcium stearate or other metallic stearate, talc, waxes and
glycerides, light mineral oil, PEG, glyceryl behenate, colloidal
silica, hydrogenated vegetable oils, corn starch, sodium stearyl
fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate,
sodium acetate etc.
[0099] Other excipients which may be included in the second
composition (and/or in the carrier composition) are e.g. colouring
agents, taste-masking agents, pH-adjusting agents, solubilizing
agents, stabilising agents, wetting agents, surface active agents,
antioxidants, agents for modified release etc.
[0100] In certain cases it may be advantageously to incorporate a
magnesium aluminometasilicate in the particulate material. It may
be a part of the second composition or it may be added subsequently
in order to facilitate a further processing of the particulate
material (e.g. to prepare solid dosage forms like capsules or
tablet). Magnesium aluminometasilicate is sold under the name
Neusilin and is obtainable from Fuji Chemical Industries. Neusilin
is normally used in order to improve filling capacity and
compression property of powders and granules when added. Neusilin
is also believed to reduce weight variation and to improve hardness
and disintegration of tablets. Finally, Neusilin has an adsorption
capability, which makes it suitable for use when processing waxy
materials like oil extracts and waxes into pharmaceutical
composition. Especially Neusilin UFL2 and US2 are said to be
suitable for such a use.
[0101] Thus, in one aspect the invention relates to a process,
wherein the second composition comprises magnesium aluminosilicate
and/or magnesium aluminometasilicate such as, e.g, Neusilin S1,
Neusilin FH2, Neusilin US2, Neusilin UFL2 or the like. Other
suitable substances are contemplated to be bentonite, kaolin,
magnesium trisilicate, montmorillonite and/or saponite. In a still
further embodiment, the second composition comprises magnesium
aluminosilicate and/or magnesium aluminometasilicate such as, e.g,
Neusilin, and the particulate material obtained has an content of
carrier of at least about 30% v/v such as, e.g, at least about 40%
v/v, at least about 50% v/v, at least about 60% v/v, at least about
70% v/v, at least about 75% v/v, at least about 80% v/v, at least
about 85% v/v or at least about 90% v/v.
[0102] Besides the known use of Neusilin, the present inventors
have found that specific qualities of magnesium aluminometasilicate
(Neusilin) have excellent properties as glidants or anti-adhesive
most likely due to the porous structure of Neusilin. Thus, Neusilin
may advantageously be added in order to reduce any adherence of the
particulate material to the manufacturing equipment in particular
to the tabletting machine. In the examples herein is given a
comparison of the anti-adhesive properties of Neusilin compared
with known lubricants and Neusilin seems to be a very promising and
novel candidate as a lubricant.
Details on Controlled Agglomeration
[0103] A process according to the invention may be carried out in a
high or low shear mixer or in a fluid bed. Important
characteristics are that the carrier or the carrier composition is
sprayed on the second composition, which is loaded into the mixer
or the fluid bed. Normally, the carrier or the carrier composition
is heated to a temperature above the melting point of the carrier
and/or the carrier composition and the second composition has not
been subject to any heating and has normally ambient temperature.
The difference in temperature between the carrier and the second
composition makes the carrier solidify rapidly which in turn leads
to a controlled growth of the particle size. Thus, the inventors
have found that by employing such conditions it is possible to
control the agglomeration process so that the growth in particle
size is controlled.
[0104] In the present context, the term "controlled agglomeration"
is intended to mean that the increase in mean geometric diameter of
a material is a linear or approximated linear function of the
carrier concentration in the carrier composition (see FIG. 1).
Controlled agglomeration is also present if a d.sub.gw of <
or=500 .mu.m is obtained when a carrier composition containing 20%
carrier has been added to a second composition.
[0105] The possibility of controlling the agglomeration makes it
possible to obtain a particulate material that has a very high load
of carrier(s)--much higher than described when conventional methods
like e.g. melt granulation is employed. As discussed above, a high
load of carrier has shown to be of importance especially when
particulate material is prepared containing a slightly
water-soluble, sparingly water soluble or insoluble active
substances. FIG. 2 is a theoretically calculated curve showing the
relationship between obtainable dose and drug solubility in a
carrier composition at different carrier concentrations in the
particulate material assuming a total composition weight of 500 mg.
It is seen that the dose can be increased by a factor of about 3.5
by increasing the concentration of carrier from 20% to 70%. By
conventional melt granulation, i.e. a process by which heating of a
melt binder and excipients is performed, normally a load of at the
most about 15% w/w of the melt binder is obtained (calculated on
the final composition). Another granulation method, which makes use
of the same temperature of the binder and the material to be
granulated, is a conventional granulation process, which is
performed either by a wet or a dry granulation process.
[0106] A SEM micrograph in FIG. 3 shows a particulate material
prepared by a process according to the present invention. PEG 6000
is used as a carrier and lactose is used as the second composition.
The figure shows that the primary particles of lactose are
agglomerated by immersion in the droplets of PEG 6000 or by
coalescence between larger agglomerates. The agglomerates are
partly coated with PEG 6000. The probability of agglomerate growth
by coalescence is reduced by rapidly solidifying PEG due to the
product temperature being kept at a minimum of 10.degree. C. below
the melting point of PEG.
[0107] In contrast thereto, uncontrolled agglomeration is shown in
a SEM micrograph in FIG. 4. The particulate material is prepared
according to Example 2 herein (uncontrolled agglomeration) using
PEG 6000 as carrier and lactose as excipients. The figure shows
that the particulate material has larger agglomerates with surplus
of liquefied PEG at the surface of the agglomerates increasing the
probability of agglomerate growth by coalescence at elevated
product temperature.
[0108] A process according to the invention may be carried out in a
fluid bed. In such cases the second composition is normally kept in
a fluidized state by incoming air at ambient temperature. The
carrier or carrier composition is sprayed on the fluidized second
composition and in order to keep the carrier or carrier composition
on a liquid form and/or to avoid any clotting of the spraying
device, the spraying device is kept at a suitable temperature above
the melting point of the carrier or carrier composition. Normally,
the spraying is performed through a spraying device equipped with
temperature controlling means.
[0109] The particulate material obtained by a process of the
invention has a geometric weight mean diameter d.sub.gw of
.gtoreq.10 .mu.m such as, e.g, .gtoreq.20 .mu.m, from about 20 to
about 2000, from about 30 to about 2000, from about 50 to about
2000, from about 60 to about 2000, from about 75 to about 2000 such
as, e.g. from about 100 to about 1500 .mu.m, from about 100 to
about 1000 .mu.m or from about 100 to about 700 .mu.m. In specific
embodiments the geometric weight mean diameter d.sub.gw is at the
most about 400 .mu.m or at the most 300 .mu.m such as, e.g., from
about 50 to about 400 .mu.m such as, e.g., from about 50 to about
350 .mu.m, from about 50 to about 300 .mu.m, from about 50 to about
250 .mu.m or from about 100 to about 300 .mu.m.
Particulate Material--Characteristics
[0110] Many characteristics of the particulate material obtained by
a process according to the invention have already been discussed.
In summary, a particulate material has good tabletting properties
including good flowability and compactability. It has no or minimal
adherence to the tabletting equipment either in itself or after
addition of the normal amount of lubricants. It is an excellent
alternative for incorporation of active substances with very low
water solubility and/or with a very low bioavailability, or active
substances, which are subject to degradation in the presence of
water (the process may be carried out without any water).
[0111] Thus, a particulate material of the invention is excellent
for a further processing into e.g. tablets. In contrast to
capsules, tablets are normally easier and cheaper to produce and
tablets are often preferred by the patient. Furthermore, a tablet
formulation is relatively easy to adjust to specific requirements,
e.g. with respect to release of the active substance, size etc.
[0112] The particulate material may also be coated (see Examples)
with a film coating, an enteric coating, a modified release
coating, a protective coating, an anti-adhesive coating etc.
[0113] Suitable coating materials are e.g. methylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic
polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl
acetate phthalate, hydroxypropyl methylcellulose phthalate,
polyvinylalcohol, sodium carboxymethylcellulose, cellulose acetate,
cellulose acetate phthalate, gelatin, methacrylic acid copolymer,
polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba
wax, microcrystalline wax, zein.
[0114] Plasticizers and other ingredients may be added in the
coating material. The same or different active substance may also
be added in the coating material.
Pharmaceutical Compositions
[0115] The particulate material obtained by a process according to
the invention may be used as such or it may be further processed to
the manufacture of a pharmaceutical and/or a cosmetic composition
by addition of one or more suitable pharmaceutically and/or
cosmetically acceptable excipients. Furthermore, the particulate
material obtained may be provided with a coating to obtain coated
particles, granules or pellets. Suitable coatings may be employed
in order to obtain composition for immediate or modified release of
the active substance and the coating employed is normally selected
from the group consisting of film-coatings (for immediate or
modified release) and enteric coatings or other kinds of modified
release coatings, protective coatings or anti-adhesive coatings
[0116] The particulate material obtained by a process of the
invention is especially suitable for further processing into
tablets. The material possesses suitable properties for tabletting
purposes, cf. below, but in some cases it may be suitable to add
further therapeutically and/or prophylactically active substances
and/or excipients to the particulate material before the
manufacture of tablets. For examples, by using a mixture of i) an
active substance contained in modified release coated granules or
granules in the form of modified release matrices and ii) an active
substance in freely accessible form, a suitable release pattern can
be designed in order to obtain a relatively fast release of an
active substance followed by a modified (i.e. often prolonged)
release of the same or a different active substance.
[0117] As appears from the above, a particulate material obtained
by a process of the invention is suitable for use in the
manufacture of tablets obtained by direct compression. Furthermore,
the particulate material may in itself be employed as a binding
agent for use in dry granulation processes.
[0118] A particulate material obtained by a process according to
the invention may be employed in any kind of pharmaceutical
compositions in which the use of a solid particulate material is
applicable. Thus, relevant pharmaceutical compositions are e.g.
solid, semi-solid, fluid or liquid composition or compositions in
the form of a spray. The particulate material may also be
incorporated in a suitable drug delivery device such as, e.g. a
transdermal plaster, a device for vaginal use or an implant.
[0119] Solid compositions include powders, and compositions in
dosage unit form such as, e.g. tablets, capsules, sachets,
plasters, powders for injection etc.
[0120] Semi-solid compositions include compositions like ointments,
creams, lotions, suppositories, vagitories, gels, hydrogels, soaps,
etc.
[0121] Fluid or liquid compositions include solutions, dispersions
such as, e.g., emulsions, suspension, mixtures, syrups, etc.
[0122] Accordingly, the invention also relates to any
pharmaceutical composition comprising a particulate material
obtainable by a process of the invention.
Other Aspects of the Invention
[0123] The invention also relates to a pharmaceutical particulate
material obtained by mixing a first and a second composition as
defined herein and heating to a temperature that is below the
melting point of a carrier contained in the first composition. The
heating may be applied while mixing or in a separate step. The
particulate material generally has a geometric weight mean diameter
d.sub.gw of .gtoreq.10 .mu.m such as, e.g. .gtoreq.20 .mu.m, from
about 20 to about 2000, from about 30 to about 2000, from about 50
to about 2000, from about 60 to about 2000, from about 75 to about
2000 such as, e.g. from about 100 to about 1500 .mu.m, from about
100 to about 1000 .mu.m or from about 100 to about 700 .mu.m, or at
the most about 400 .mu.m or at the most 300 .mu.m such as, e.g.,
from about 50 to about 400 .mu.m such as, e.g., from about 50 to
about 350 .mu.m, from about 50 to about 300 .mu.m, from about 50 to
about 250 .mu.m or from about 100 to about 300 .mu.m. In such a
material the concentration of the carrier typically is at least
about 40% v/v.
[0124] Such a particulate material is especially suitable for use
in the preparation of solid dosage form such as tablets, capsules,
sachets and the like. It may have sufficient properties with
respect to flowability and/or anti-adhesion so that addition of
e.g. a lubricant can be omitted when preparing a solid dosage form,
especially if it comprises magnesium aluminosilicate and/or
magnesium aluminometasilicate.
[0125] In a further aspect, the invention relates to the use of
magnesium aluminosilicate and/or magnesium aluminometasilicate as a
lubricant.
[0126] All details described herein for the main aspect of the
invention apply mutatis mutandi to any other aspect of the
invention.
LEGENDS TO FIGURES
[0127] FIG. 1 shows the correlation between amount of PEG 6000
sprayed onto lactose 125 mesh and mean granule size (geometric
weight mean diameter) for a product temperature of 40-45.degree. C.
and 50-60.degree. C., respectively. The dashed line indicates
uncontrolled agglomeration at a PEG concentration of approx. 25% at
a product temperature of 50-60.degree. C. The products are
unscreened.
[0128] FIG. 2 shows the relationship between obtainable dose and
drug solubility in a carrier at different concentrations of carrier
assuming a formulation unit weight of 500 mg.
[0129] FIG. 3 is a SEM micrograph of PEG sprayed onto lactose 125
mesh; the PEG concentration is 48% w/w. Magnification
.times.45.
[0130] FIG. 4 is a SEM micrograph of PEG sprayed onto lactose 125
mesh; the PEG concentration is 25% w/w. Magnification
.times.45.
[0131] FIG. 5 shows results from Example 4.
[0132] FIG. 6 shows mean serum concentrations vs. time profiles
after p.o. administration of the model drug substance from Example
5 (30 mg) in six different formulations to Beagle dogs. Treatment
A: 0.5% HPC (aq.), Treatment B: 5% Captisol.RTM. (aq.), Treatment
C: Model drug substance from Example 5/SLS (2:1), Treatment D:
Model drug substance from Example 5/SLS (1:1), Treatment E: Tween
80, Kollidon VA64, corn starch and lactose, Treatment F:
Akosoft.RTM. 3103.
[0133] FIG. 8 illustrates determination of a melting point by a DSC
curve.
[0134] The inventon is further illustrated in the following
examples.
METHODS
Determination of Weight Variation
[0135] The tablets prepared in the Examples herein were subject to
a test for weight variation performed in accordance with Ph.
Eur.
Determination of Average Tablet Hardness
[0136] The tablets prepared in the Examples herein were subject to
at test for tablet hardness employing Schileuniger Model 6D
apparatus and performed in accordance with the general instructions
for the apparatus.
Determination of Disintegration Time
[0137] The time for a tablet to disintegrate, i.e. to decompose
into particles or agglomerates, was determined in accordance with
Ph. Eur.
Determination of Geometric Weight Mean Diameter d.sub.gw
[0138] The geometric weight mean diameter was determined by
employment of a method of laser diffraction dispersing the
particulate material obtained (or the starting material) in air.
The measurements were performed at 1 bar dispersive pressure in
Sympatec Helos equipment, which records the distribution of the
equivalent spherical diameter. This distribution is fitted to a log
normal volume-size distribution.
[0139] When used herein, "geometric weight mean diameter" means the
mean diameter of the log normal volume-size distribution.
Determination of Aqueous Solubility
[0140] The aqueous solubility at 25.degree. C. in distilled or
purified water was determined by suspending a well-defined and
excessive amount of the substance under investigation in a
well-defined amount of distilled or purified water. The dispersion
is stirred and samples are withdrawn after suitable time periods.
The samples are filtered and the filtrate analysed to obtain the
concentration of the substance in the sample. The concentration of
the substance in the sample is then calculated according to methods
well known for a person skilled in the art. The solubility is
reached when the concentrations of the substance in two consecutive
samples are considered identical.
Determination of Dissolution Rate
[0141] The dissolution rate was determined by employment of USP
paddle dissolution method at 37.degree. C.
Materials
[0142] All materials employed were of pharmaceutical grade.
Calcium hydrogen phosphate (Di-cafos A): Budenheim
Croscarmellose Sodium Ac-Di-Sol: FMC
Magnesium stearate: Magnesia GmbH
Polyethylene glycol: Hoechst
Lactose: DMV
[0143] Other materials employed appear from the following
examples.
EXAMPLES
Example 1
Preparation of Tablets Containing a Particulate Material According
to the Invention
[0144] The example illustrates the preparation of a particulate
material comprising a relatively large amount of a carrier. The
particulate material obtained exhibits good flowability, good
compactability and possesses excellent tabletting properties. Thus,
the particulate material allow the preparation of e.g. tablets and
in spite of the relatively large load of carrier the tablets
display minimal, if any, adherence (sticking) to tablet punches
and/or dies during compression. Furthermore, the tablets obtained
have acceptable properties with respect to disintegration, weight
variation and hardness.
Starting Materials
Lactose monohydrate (DMV) 125 mesh
Calcium hydrogen phosphate anhydrous (Di-Ca-Fos P)
Polyethylene glycol 6000 (PEG 6000) having a melting point of about
60.degree. C.
Equipment
[0145] Fluid bed Strea-1 (from Aeromatic-Fielder) mounted with a
special developed top-spray binary nozzle having an opening of 0.8
mm.
[0146] Granular Compositions TABLE-US-00003 Composition 1.1 Lactose
500 g PEG 6000 420 g (sprayed on lactose)
[0147] The composition has a carrier concentration of 45.6% w/w.
TABLE-US-00004 Composition 1.2 Calcium hydrogen phosphate anhydrous
500 g PEG 6000 210 g (sprayed on calcium hydrogen phosphate)
[0148] The composition has a carrier concentration of 29.6%
w/w.
Process Conditions--Description
[0149] Lactose (or for composition 1.2 calcium hydrogen phosphate
anhydrous) was fluidised at appropriate inlet airflow. The inlet
air was not heated. PEG 6000 was melted using an electrically
heated pressure tank. The temperature was kept at a temperature at
about 85.degree. C., i.e. above the melting point of PEG 6000. The
melt was pumped from the tank to the nozzle through a heated tube.
In the tube, the temperature was kept at 80.degree. C. The pressure
in the tank determined the flow rate of the melt. The nozzle was
heated to keep the droplets in a liquefied stage by means of
heating the atomizer air delivered through the top-spray
nozzle.
Settings
Inlet airflow: 30-50 m.sup.3 per hour
Inlet air temperature: Ambient temperature (20-25.degree. C.)
Tank temperature: 85.degree. C.
Tank pressure: 1.5 Bar corresponding to a flow rate of 14-15
g/min
Tube temperature: 80.degree. C.
Atomising air temperature: 100.degree. C.
Process time: 28 min
Product temperature at equilibrium: 40.degree. C. (after 15
minutes)
Product Characteristics
[0150] The products (composition 1.1 and 1.2) appear as free
flowing granular products with a mean granule size of approx.
300-500 .mu.m.
Tabletting
[0151] Compositions TABLE-US-00005 Tablet formulation I (without
disintegrant) Granular product 99% w/w Magnesium stearate 1%
w/w
[0152] The tablet formulation has a carrier concentration of 45.2%
w/w. TABLE-US-00006 Tablet formulation II (with disintegrant)
Granular product 95% w/w Ac-Di-Sol (croscarmelose sodium) 4% w/w
(disintegrant) Magnesium stearate 1% w/w
[0153] The tablet formulation has a carrier concentration of 28%
w/w.
Tablet Properties
Tablet formulation I based on composition 1.1, i.e. with
lactose
Tablet punch: Compound cup, 10 mm in diameter
Tablet machine: Single punch machine Korsch EK0
Tablet weight: 250 mg
Weight variation, RSD<1%
Average tablet hardness: 96 N
Average disintegration time: 10 min
Tablet appearance: White glossy tablets
Tablet formulation I based on composition 1.2, i.e. with dicalcium
phosphate
Tablet punch: Compound cup, 10 mm in diameter
Tablet machine: Single punch machine Korsch EK0
Tablet weight: 450 mg
Weight variation, RSD<1%
Average tablet hardness: 121 N
Average disintegration time: 17 min
Tablet appearance: White glossy tablets
Tablet formulation II based on composition 1.1, i.e. with
lactose
Tablet punch: Compound cup, 10 mm in diameter
Tablet machine: Single punch machine Korsch EK0
Tablet weight: 250 mg
Weight variation, RSD<1%
Average tablet hardness: 112 N
Average disintegration time: 8 min
Tablet appearance: White glossy tablets
[0154] Thus, addition of a disintegrant results in a decrease in
the average disintegration time without any other changes of
importance.
Tablet formulation II based on composition 1.2, i.e. with calcium
hydrogen phosphate
Tablet punch: Compound cup, 10 mm in diameter
Tablet machine: Single punch machine Korsch EK0
Tablet weight: 450 mg
Weight variation, RSD<1%
Average tablet hardness: 118 N
Average disintegration time: 9 min
Tablet appearance: White glossy tablets
[0155] When calcium dihydrogen phosphate anhydrous is employed a
more pronounced decrease in disintegration time is observed
compared with that of lactose. The average tablet hardness is
maintained at an excellent level.
Example 2
Controlled Agglomeration--Proof of Concept
Method
[0156] Controlled agglomeration is obtained by keeping the product
temperature at minimum 10.degree. C. below melting point of the
carrier reducing the probability of agglomeration due to
coalescence. Controlled agglomeration is characterised by gradual
increase in mean granule size (geometric weight mean diameter
d.sub.gw) as function of applied amount of carrier. In contrast,
uncontrolled agglomeration shows rapidly increasing granule size.
As a proof of concept the granule growth pattern are compared
corresponding to the following conditions: [0157] Inlet fluidising
air temperature of ambient temperature: 20-25.degree. C. [0158]
Inlet fluidising air temperature of 85.degree. C. leading to a
temperature of the product of about 50-60.degree. C., Starting
Materials Lactose monohydrate 125 mesh Polyethylene glycol 6000
Equipment Fluid bed Strea-1 mounted with a top-spray binary nozzle.
Granular Compositions Lactose 400 g PEG 6000 Increased stepwise in
separate experiments (from 0% to about 60% w/w in the final
composition) Process Conditions
[0159] The conditions were the same as described in Example 1.
Settings (Controlled Agglomeration)
Inlet airflow: 30-50 m.sup.3 per hour
Inlet air temperature: Ambient temperature (20-25.degree. C.)
Tank temperature: 90.degree. C.
Tank pressure: 1.5 Bar corresponding to a flow rate of 14-15
g/min
Tube temperature: 85.degree. C.
Atomizer air temperature: 100.degree. C.
Product temperature at equilibrium: 40.degree. C.
Settings (Uncontrolled Agglomeration)
Inlet airflow: 30-50 m.sup.3 per hour
Inlet air temperature: 85.degree. C.
Tank temperature: 90.degree. C.
Tank pressure: 1.5 Bar corresponding to a flow rate of 14-15
g/min
Tube temperature: 85.degree. C.
Atomizer air temperature: 100.degree. C.
Product temperature at equilibrium: 55-65.degree. C.
Product Characteristics
[0160] Increasing amounts of PEG were sprayed onto the fluidised
lactose particles and the particle size distribution of the
products was analysed by method of laser diffraction, dispersing
the agglomerates in air. The correlation between mean granule size
(geometric weight mean diameter d.sub.gw) and applied amount of
carrier demonstrates the difference between controlled and
uncontrolled agglomeration as shown in FIG. 1 and Table 1. Table 1
includes the geometric standard deviation s.sub.g related to the
wideness of the size distribution. TABLE-US-00007 Product
temperature 40-45.degree. C. Product temperature 50-60.degree. C.
Inlet air temperature: Ambient Inlet air temperature: 85.degree. C.
PEG, PEG w/w % D.sub.gw, .mu.m S.sub.g w/w % D.sub.gw, .mu.m
S.sub.g 0 55 2.37 0 55 2.37 17 151 2.09 13 343 1.98 26 261 2.09 15
513 1.48 38 328 2.06 25 980 1.43 48 332 1.95 60 450 1.8
[0161] Table 1. Particle size characteristics of granulate products
produced by agglomeration by melt spraying in fluid bed at heated
and unheated inlet air conditions at different applied amount of
PEG 6000 concentrations. D.sub.gw: Geometric weight mean diameter.
S.sub.g: Geometric standard deviation.
Example 3
Improving Tabletting Characteristics of Paracetamol Applying the
Controlled Agglomeration Technique
[0162] Parcetamol has been chosen as model substance representing a
substance with poor compression characteristics. By incorporation
of PEG 6000 by melt spraying, i.e. spraying melted PEG 6000 on
paracetamol, a granular product of paracetamol is obtained with
excellent flowability and tablet compression characteristics.
In order to obtain tablets with satisfactory disintegration time
Avicel PH 200 and Kollidon CL (super-disintegrant) has been added
to the product
Starting Materials
Polyethyleneglycol 6000 (Hoechst)
Paracetamol (Unikem)
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0163] 300 g PEG 6000 was melted by heating to 90.degree. C. in a
pressure tank. The melted carrier was pumped through a heated tube
(85.degree. C.) to the binary nozzle in the fluid bed at a tank
pressure of 1.5 Bar. The atomizing air was heated to 140.degree. C.
The inlet air temperature of the fluid bed was 25.degree. C.
[0164] 241 g of PEG was sprayed on 250 fluidized paracetamol at a
flow rate of 17 g/min. The total yield was 491 g granulate with a
composition corresponding to 49.1% w/w PEG 6000 and 50.9% w/w
paracetamol. The maximum product temperature was 36.degree. C. at
the end of the process.
Product Characteristics
[0165] The median particle size on volume basis is 85 .mu.m for
paracetamol was increased to 295 .mu.m during the controlled
agglomeration process. The median particle size was determined by
laser diffraction (Helos) dispersing the particles in air.
TABLE-US-00008 Tablet composition Paracetamol 44% PEG 6000 41%
Avicel PH200 10% Kollidon CL 4% Magnesium stearate 1%
[0166] Paracetamol and PEG 6000 are employed in the form of the
granular product obtained as described above.
[0167] Avicel PH is blended with the granular product for 2 minutes
in Turbula mixer and after adding magnesium stearate for further
0.5 minutes. Avicel PH200 (microcrystalline cellulose) is supplied
by FMC, Kollidon CL by BASF and magnesium stearate by Magnesia
GmbH.
Tabletting and Tablet Characteristics
The tabletting was performed on a single punch tabletting machine
Korsch EK0
Tablet shape 8 mm doomed shape
Weight: 200 mg
Strength 87 mg
Mean tablet hardness (n=10) determined on a Schleuninger Model 6D
apparatus was 77 N
Friability was 0.2% determined at a Roche friabililator
Mean disintegration time was 11 minutes (Ph.Eur)
Weight variation (n=20) corresponded to RSD of 0.6%
[0168] In conclusion, the tablets obtained from the granulate
prepared by the controlled agglomeration method of the invention
were very satisfactory and only a relatively small concentration of
tabletting excipients was needed in order to ensure a suitable
tabletting process. Furthermore, the example demonstrates that it
is possible to obtain a granulate that has a relatively high
concentration of carrier (about 50% w/w) and at the same time has a
suitable particle size for further processing.
Example 4
In Vivo Bioavailability in Dogs after Administration of Tablets
Containing a Particulate Material Obtained by the Controlled
Agglomeration Method of the Present Invention--Proof of Concept
[0169] The present example illustrates that a composition
containing a particulate material obtained according to the present
invention leads to improved bioavailability after oral
administration to dogs compared with compositions made by
techniques that are generally accepted as useful when an increase
in bioavailability is desired. In the present example compositions
in the form of a nanosuspension and a microemulsion are used for
comparison.
[0170] The model drug substance employed illustrates a drug
substance that has a very low aqueous solubility of less than 50
ng/ml independent on pH. The molecular weight of the model drug
substance is about 600 and it has a lipophilicity i.e. a log P
(octanol/water) of 5.0.
[0171] Proof of concept is based on a comparison of bioavailability
of different oral formulations and an I.V. injection of the drug
substance in dogs (n=4). Data on the I.V. is not included in this
example.
Treatment Compositions and Treatment Schedule
[0172] Treatment A (comparison treatment): nanosuspension
containing 2% w/w of the model drug substance. NanoCrystal.TM.
colloidal suspension of the model drug substance stabilised with
hydroxy propyl cellulose (HPC-SL). Supplier: Elan pharmaceutical
technologies, USA. EPT Ref. NB: GOT-5747-170. The nano-suspension
contains 2% of the model drug substance and 1% HPC-SL (w/w). A
treatment consisted in oral administration of 36.3 mg as a single
dose (approximately 1.8 ml).
[0173] Treatment B (according to the invention): tablets containing
a particulate material obtained according to the method of the
present invention. The tablets contain about 1% w/w of the model
drug substance. The preparation of the composition used in
Treatment B is described below. A treatment consisted in oral
administration of 6 tablets as a single dose corresponding to
approx. 37.5 mg.
[0174] Treatment C (according to the invention): tablets containing
a particulate material obtained according to the method of the
present invention. The tablets contain about 5% w/w of the model
drug substance. The preparation of the composition used in
Treatment C is described below. A treatment consisted in oral
administration of 2 tablets as a single dose corresponding to
approx. 42.4 mg.
[0175] Treatment D (comparison treatment): capsules containing a
microemulsion of the model drug substance. Soft gelatine capsules
containing 7.3 mg of the model drug substance in a vehicle
consisting of 40% w/w Softigen 767, 15% w/w trietylcitrate and 45%
w/w polysorbate 80 (0.05% BHA was added by weight as antioxidant).
A treatment consisted of a single dose of 5 capsules, equivalent to
36.5 mg of the model drug substance.
[0176] Treatment E (comparison treatment): capsules containing a
microemulsion of the model drug substance. Soft gelatine capsules
containing 12.43 mg of the model drug substance in a vehicle
consisting of 40% w/w Softigen 767, 15% w/w trietylcitrate and 45%
w/w polysorbate 80 (0.05% BHA was added by weight as antioxidant).
A treatment consisted of a single dose of 3 capsules, equivalent to
37.2 mg of the model drug substance.
Preparation of a Pharmaceutical Composition According to the
Invention Used in Treatment B (5 mg Model Drug Substance)
Preparation of a Particulate Material--Melt-Spraying Process
Starting Materials
Polyethyleneglycol 6000 (Hoechst)
Poloxamer 188 (BASF)
Model drug substance
Avicel PH 101 (FMC)
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0177] 198.0 g PEG 6000 and 85.0 g Poloxamer 188 (70:30 w/w) were
melted by heating to 75.degree. C. in a pressure tank. 6.21 g model
drug substance was dissolved in the melted carriers. The melt was
pumped through a heated tube (80.degree. C.) to the binary nozzle
in the fluid bed at a tank pressure of 1.8 Bar. The atomizing air
was heated to 140.degree. C. The inlet air temperature of the fluid
bed was 22.degree. C.
[0178] 289 g of melt was sprayed on 300 g fluidized Avicel PH 101
at a flow rate of 10 g/min. The total yield was 589 g granulate.
The maximum product temperature was 36.degree. C. at the end of the
process.
Product Characteristic
[0179] Granular, free flowing product with a particle size under
0.7 mm.
Tablet Composition (w/w)
[0180] Tablets were obtained by compression of a powder blend
containing the granulate obtained as described above with magnesium
stearate. TABLE-US-00009 Model drug substance 1.04% PEG 6000 33.26%
Poloxamer 188 14.29% Avicel PH101 50.41% Magnesium stearate
1.00%
[0181] Magnesium stearate was blended with the granulate for 0.5
minutes in a Turbula-mixer.
Tabletting and Tablet Characteristics
The tabletting was performed on a single punch tabletting machine
Korsch EK0
Tablet shape 11.5 mm doomed shape
Weight: 515 mg
Strength 5 mg
Mean tablet hardness (n=10) determined on a Schleuninger Model 6D
apparatus was 105 N
Mean disintegration time was 21.5 minutes (Ph.Eur)
Weight variation (n=20) corresponded to RSD of 0.9%
Preparation of a Pharmaceutical Composition According to the
Invention Used in Treatment C (20 mg Model Drug Substance)
Preparation of a Particulate Material--Melt-Spraying Process
Starting Materials
Polyethyleneglycol 6000 (Hoechst)
Poloxamer 188 (BASF)
Model drug substance
Avicel PH 101 (FMC)
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0182] 121.9 g PEG 6000 and 52.3 g Poloxamer 188 (70:30 w/w) were
melted by heating to 75.degree. C. in a pressure tank. 20.96 g
model drug substance was dissolved in the melted carriers. The melt
was pumped through a heated tube (80.degree. C.) to the binary
nozzle in the fluid bed at a tank pressure of 1.8 Bar. The
atomizing air was heated to 140.degree. C. The inlet air
temperature of the fluid bed was 22.degree. C.
[0183] 195 g of melt was sprayed on 200 g fluidized Avicel PH 101
at a flow rate of 11.4 g/min. The total yield was 395 g granulate.
The maximum product temperature was 37.degree. C. at the end of the
process.
Product Characteristic
[0184] Granular, free flowing product with a particle size under
0.7 mm.
Tablet Composition (w/w)
[0185] Tablets were obtained by compression of a powder blend
containing the granulate obtained as described above with magnesium
stearate. TABLE-US-00010 Model drug substance 5.26% PEG 6000 30.54%
Poloxamer 188 13.11% Avicel PH101 50.09% Magnesium stearate
1.00%
[0186] Magnesium stearate was blended with the granulate for 0.5
minutes in a Turbula-mixer.
Tabletting and Tablet Characteristics
The tabletting was performed on a single punch tabletting machine
Korsch EK0
Tablet shape 11.5 mm doomed shape
Weight: 409 mg
Strength 20 mg
Mean tablet hardness (n=10) determined on Schleuninger Model 6D
apparatus was 41 N
Mean disintegration time was 5.5 minutes (Ph.Eur)
Weight variation (n=20) corresponded to RSD of 1.3%
Study Design and Results
[0187] The study design was a cross-over study, which comprised all
four dogs in one group. In each of totally six weeks the dogs were
dosed orally on the first day of the week following by 6 days of
recovery. The first week the dogs were assigned to treatment A,
second week to treatment B etc.
[0188] Summary of pharmacokinetic parameters. Beagle dogs after
single oral dosing of the model drug substance (.+-.SD, n=4).
TABLE-US-00011 Treatment A B C D E t.sub.max (h) 2.2 .+-. 0.5 2.8
.+-. 0.5 4.3 .+-. 3.2 2.8 .+-. 1.3 2.0 .+-. 0.0 C.sub.max (ng/ml)
19 .+-. 8 52 .+-. 15 29 .+-. 17 35 .+-. 13 42 .+-. 6
AUC.sub.0-inf.sup.a 206 .+-. 108 489 .+-. 187 290 .+-. 184 318 .+-.
144 318 .+-. 65 (ng/ml) F.sup.b (%) 4.8 .+-. 1.9 11 .+-. 4 5.4 .+-.
2.7 7.8 .+-. 3.8 7.6 .+-. 2.9 Calculated as .sup.a AUC.sub.last +
C.sub.last * t.sub.1/2, i.v./In2; .sup.b AUC.sub.0-inf,po
D.sub.iv/(AUC.sub.0-inf,iv D.sub.po)
[0189] From the results given above it and in FIG. 5 is seen that
treatment B leads to improved bioavailability compared with all
other treatments employed. It is particularly interesting to note
that compositions containing the model drug substance in dissolved
form (treatment D and E) do not lead to a better bioavailability
than treatment B and there is no significant difference in the
t.sub.max values obtained, i.e. the onset of the therapeutic effect
is the same even if a solid composition is used. Treatment C leads
to a lower bioavailability than treatment B, which may be explained
by the fact that the ration between the amount of drug substance in
the carrier is higher in treatment C than in treatment B (higher
dose in treatment C than in treatment B).
Example 5
In Vivo Bioavailability in Dogs after Administration of Tablets
Containing a Particulate Material Obtained by the Controlled
Agglomeration Method of the Present Invention--Proof of Concept
II
[0190] The present example illustrates that a composition
containing a particulate material obtained according to the present
invention leads to improved bioavailability after oral
administration to dogs compared with compositions made by
techniques that are generally accepted as useful when an increase
in bioavailability is desired. In the present example compositions
in the form of a nanosuspension and a cyclodextrin solution are
used for comparison.
[0191] The model drug substance employed illustrates a drug
substance that has a very low aqueous solubility of about 50
.mu.g/ml in phosphate buffer pH 7.4. The model drug substance in
this example has a pK.sub.A of 8, a molecular weight of about 450
and a lipophilicity i.e. a log P (octanol/buffer pH 7.4) of 6.0.
The model drug substance is employed in the form of a hydrochloride
salt. The aqueous solubility of the salt is also very low.
[0192] The results presented below are based on absorption study in
dogs comparing 6 different formulations.
Formulation A (nanosuspension)
Formulation B: Cyclodextrin solution (Captisol)
Formulation C: Mixture of SLS and the model drug substance
(0.5:1)
Formulation D: Mixture of SLS and the model drug substance
(1:1)
Formulation E: Granulate with 10% Tween 80
Formulation F: (granulate in capsule) prepared by a method
according to the present invention by melt spraying and using
Akosoft XP 3103.
[0193] A summary of the pharmacokinetic report on the study is
given below.
[0194] Test formulation A was prepared by suspending nanonised
model drug substance particles in a vehicle of 0.5% HPC(HPC)
(Klucel.RTM. MF EP, Hercules Inc.) and purified water. A similar
suspension was included in an initial study where it resulted in a
mean relative bioavailability of only 0.64 when compared to a 5%
Capbsol.RTM. solution. However, it was suspected that the initial
suspension used was not optimal, as the particle size distribution
was above the micrometer range. Subsequently, the micronisation
process has been optimised, and test formulation A was prepared
from a model drug substance batch, which contained particles in the
nanometer range. Reference formulation B was prepared by dissolving
the model drug substance in an aqueous vehicle of 5%
.beta.-cyclodextrin sulfobutyl ether, sodium salt (Captisol.RTM.,
CyDex Inc).
[0195] Test formulation C was prepared by dissolving sodium lauryl
sulphate (SLS) in water and adding the solution to the model drug
substance drop by drop (model drug substance/SLS w/w-ratio 2:1).
The dried mixture and lactose were filled in capsules.
[0196] Test formulation D was prepared by dissolving SLS in water
and adding the solution to the model drug substance drop by drop
(model drug substance/SLS w/w-ratio 1:1). The dried mixture and
lactose were filled in capsules.
[0197] Test formulation E was prepared by melt granulation of the
model drug substance, 10% Tween 80, 2% Kollidon VA64, corn starch
and lactose. The granulate was filled in capsules.
[0198] Test formulation F was prepared by a method of the invention
by melt spraying the model drug substance, Akosoft 3103 and
lactose. The granulate obtained was filled in capsules. Akosoft
3103 is a mixture of Akoline HH(C.sub.8-C.sub.10 monoglycerides),
Akosoft 36 (hydrogenated cocoglyceride) and Akofine NF
(hydrogenated cottonseed oil) from Karlshamns AB. All are saturated
fats or oils, i.e. no double-bonds, PEG-chains or free acid groups
exist in the excipients.
[0199] In the following the preparation of test formulation F is
described in further details.
Test Formulation F
Preparation of a Particulate Material--Melt-Spraying Process
Starting Materials
Akosoft XP 3103 (Karlshamn)
Model drug substance
Lactose 350 M (DMV)
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0200] 153 g Akosoft XP 3103 was melted by heating to 70.degree. C.
in a pressure tank. The melt was pumped through a heated tube
(80.degree. C.) to the binary nozzle in the fluid bed at a tank
pressure of 0.3 Bar. The atomizing air was heated to 140.degree. C.
The inlet air temperature of the fluid bed was 22.degree. C.
[0201] 114 g of melt was sprayed on fluidized material consisting
of 256.5 g lactose 350 M and 43.5 g model drug substance at a flow
rate of 30 g/min. The total yield was 414 g granulate. The maximum
product temperature was 32.degree. C. at the end of the
process.
Product Characteristic
Granular product with a particle size under 0.7 mm.
The product was filled into capsules (500 mg corresponding to 30 mg
base)
Study Design and Dosing
[0202] The study was conducted in a cross-over design. After a five
days pre-dose period the test formulations were administered in
intervals of three or four days. Test formulations were
administered in the order B, A, C, D, E and F.
[0203] On days of dosing each dog was dosed in the morning with 30
mg of the model drug substance (with regard to the base)
irrespective of bodyweight. The dose level chosen was based on
previous studies with the model drug substance in Beagle dogs.
Pharmacokinetic Results
[0204] Mean serum concentrations vs. time are presented in FIG. 6.
Standard deviations are omitted in the figure for clarity. The data
is shown in the Table below
[0205] The concentration of the model drug substance in the serum
sample taken from dog F1131 at 24 hours is high compared to the
concentrations observed at previous time points. Re-analysis
confirmed the result and the late serum concentration increase
might therefore be due to delayed absorption of the test
compound.
[0206] Pharmacokinetic parameters for the model drug substance
estimated by standard non-compartmental analysis are given in the
following Table.
[0207] For the reference solution a mean t.sub.max of 2.5 hours was
observed. The other treatments resulted in mean t.sub.max values of
2.3 hours (HPC--formulation A), 3.0 hours (model drug substance/SLS
2:1--formulation C), 3.8 hours (Akosoft 3103--formulation F), 4.8
hours (Tween 80/Kollidon VA64--formulation E) and 8.3 hours (model
drug substance/SLS 1:1--formulation D). The latter mean t.sub.max
value is high due to the extreme contribution from dog F1131 (see
above). If this data point is omitted a mean t.sub.max of 3.0 hours
is observed.
[0208] With a mean maximum serum concentration at 123 nmolL.sup.-1
the Akosoft 3103 formulation (formulation F) gave a value almost
similar to the reference solution at 124 nmolL.sup.-1. At the other
extreme the treatments with SLS (formulations C and D) resulted in
mean C values of 31.5 nmolL.sup.-1 (model drug substance/SLS 2:1)
and 50.3 nmolL.sup.-1 (model drug substance/SLS 1:1). Again the
mean value would be smaller if the 24 hours data point for
formulation D was omitted. Administration of the HPC- and Tween
80/Kollidon VA64--formulations resulted in mean C.sub.max values of
87.9 nmolL.sup.-1 and 85.3 nmolL.sup.-1, respectively.
[0209] In the Table on next page are given individual and mean
(n=4) pharmacokinetic parameters of the model drug substance
employed in Example 5 after dosing of 30 mg to Beagle dogs.
Treatment A: 0.5% HPC (aq.), Treatment B: 5% Captisol.RTM. (aq.),
Treatment C: model drug substance/SLS (2:1), Treatment D: model
drug substance/SLS (1:1), Treatment E: Tween 80, Kollidon VA64,
corn starch and lactose, Treatment F: Akosoft.RTM. 3103.
TABLE-US-00012 C.sub.max AUC.sub.0-t Dose.sup.b) t.sub.max (nmol
(nmol AUC.sub.0-inf t.sub.1/2.sup.c) CL/F V.sub.2/F
Treatment.sup.a) Animal (nmol/kg) (h) L.sup.-1) h L.sup.-1) (nmol h
L.sup.-1) AUC.sub.%residual (h) (L kg.sup.-1 h.sup.-1) (L
kg.sup.-1) F.sub.rel,inf.sup.d) F.sub.rel,t.sup.e) A F1131 4381 2.0
82.3 617 657 8.1 3.9 6.67 37.6 0.58 0.57 F1132 4440 2.0 61.3 407
418 2.7 4.3 10.8 66.2 0.52 0.52 F1138 4595 3.0 109 1025 1067 4.0
4.9 4.31 30.6 0.95 0.94 F1139 5016 2.0 99.0 751 780 3.7 4.7 6.40
44.0 1.04 1.04 Mean 2.3 87.9 700 731 4.1 4.5 7.0 44.6 0.77 0.77 CV
% 21.7 23.7 37.0 36.9 34.9 9.85 37.5 34.5 33.9 33.9 B F1131 4730
3.0 145 1163 1231 5.5 5.3 3.84 29.6 -- -- (reference) F1132 4794
3.0 101 842 873 3.5 4.7 5.49 37.2 -- -- F1138 4995 2.0 141 1180
1217 3.0 4.7 4.11 27.6 -- -- F1395 5580 2.0 107 804 832 3.4 4.7
6.71 45.4 -- -- Mean 2.5 124 997 1038 3.9 4.9 5.0 35.0 -- -- CV %
23 18 20 21 29 6.1 27 23 -- -- C F1131 4762 3.0 12.5 78 95 17 4.1
50.2 297 0.08 0.07 F1132 4794 3.0 8.63 53 66 20 4.3 73.0 455 0.08
0.06 F1138 5030 3.0 6.86 51 73 30 6.1 69.3 608 0.08 0.04 F1139 5580
3.0 98.0 781 817 4.4 4.9 6.83 48.2 0.98 0.97 Mean 3.0 31.5 241 263
17.9 4.9 60 352.1 0.30 0.29 CV % 0.0 141 150 141 58.9 18.4 61.0
67.9 151 158 D F1131 4730 24 32.5 321 610 47 6.2 7.75 68.9 0.11
0.28 F1132 4826 2.0 34.1 291 339 14 4.7 14.2 96.1 0.27 0.23 F1138
4995 3.0 27.7 236 249 5.1 5.2 20.0 150 0.20 0.20 F1139 5537 4.0 107
913 957 4.6 4.9 5.80 41.1 1.16 1.14 Mean 8.3 50.3 440 539 17.7 5.3
12 89.0 0.44 0.46 CV % 127 75.3 72.1 69.0 113 12.6 54.3 52.2 111
98.5 E F1131 4826 6.0 43.2 575 752 24 10 6.42 95.4 0.60 0.48 F1132
4859 6.0 78.8 802 835 4.0 4.5 5.62 38.1 0.94 0.94 F1138 5030 3.0
102 956 1015 5.8 5.5 4.95 39.0 0.83 0.80 F1139 5537 4.0 117 1058
1118 5.3 6.2 5.00 37.4 1.35 1.33 Mean 4.8 85.3 848 930 9.8 6.3 5.5
52.5 0.93 0.89 CV % 31.3 37.7 24.8 17.9 97.1 39.7 12.8 54.5 33.7
39.6 F F1131 4762 3.0 152 1334 1414 5.7 5.3 3.37 25.6 1.14 1.14
F1132 4826 4.0 99.1 839 867 3.3 4.4 5.56 35.1 0.99 0.99 F1138 5102
4.0 88.1 881 926 4.8 5.0 5.51 40.1 0.74 0.73 F1139 5537 4.0 153
1210 1266 4.4 4.8 4.37 30.1 1.53 1.52 Mean 3.8 123 1066 1118 4.6
4.9 4.7 32.7 1.10 1.10 CV % 13.2 27.9 22.9 23.6 21.6 7.70 22.2 19.2
30.0 31.0
[0210] Individual doses used in the pharmacokinetic analysis were
calculated by DCF/M.sub.WBW; D is the dose administered with
respect to the base (ng), M.sub.W is the molecular weight of the
model drug substance (ng/nmol), BW is the body weight of the animal
(kg) and CF is the correction factor determined from analysis of
the test formulations.
[0211] t.sub.1/2 was calculated from .lamda.-values estimated from
data points at 2-8 hours (I), 2-12 hours (II), 2-24 hours (III),
3-12 hours (IV), 3-24 hours (V), 4-24 hours (VI), 6-12 hours (VII)
and 6-24 hours (VIII) F.sub.rel,inf was calculated as
F.sub.rel=AUC.sub.0-inf.sup.testDose.sup.ref/AUC.sub.0-inf.sup.refDose.su-
p.test F.sub.rel,t was calculated as
F.sub.rel=AUC.sub.0-t.sup.testDose.sup.ref/AUC.sub.0-t.sup.refDose.sup.te-
st
[0212] Mean values for the relative bioavailability (relative to
cyclodextrin solution) were almost identical irrespective of the
calculation being made with respect to the serum concentration time
curve to infinity (AUC.sub.0-inf) or to the last measurable
concentration (AUC.sub.0-t). Mean values for the latter AUC
parameter were 997 nmolhL.sup.-1 (reference formulation), 1066
nmolhL.sup.-1 (Akosoft 3103), 848 nmolhL.sup.-1 (Tween 80/Kollidon
VA64), 700 nmolhL.sup.-1 (HPC), 440 nmolhL.sup.-1 (model drug
substance/SLS 1:1) and 241 nmolhL.sup.-1 (model drug substance/SLS
2:1). The low values for the two SLS formulations are in line with
the low C.sub.max values observed for these formulations.
[0213] The corresponding mean relative bioavailability-values were
1.10 (Akosoft 3103), 0.89 (Tween 80/Kollidon VA64), 0.77 (HPC),
0.46 (model drug substance/SLS 1:1) and 0.29 (model drug
substance/SLS 2:1).
[0214] The low relative bioavailability observed for the two
SLS-formulations was not expected as a similar formulation, albeit
with a model drug substance/SLS-ratio at 2:1, administered in a
previous study resulted in a mean relative bioavailability of 1.20.
Apparently there is a critical concentration below which the
dissolution- and absorption enhancing properties of SLS are
limited.
[0215] All formulations administered to animal F 1039 resulted in a
relative bioavailability (based on AUC.sub.0-inf) around or above
unity (range 0.98-1.53). The relative bioavailability determined in
this dog for the different formulations therefore contributes
considerably to the mean F.sub.rel. This is especially the case for
the two SLS formulations where the relative bioavailability is very
low for the other three dogs. When this dog was excluded mean
values of 0.24 and 0.06 were found for model drug
substance/SLS-ratios of 1:1 and 2:1, respectively.
[0216] The mean apparent half life determined after administration
of the various treatments were 4.5 hours (HPC suspension), 4.8
hours (5% Captisol.RTM. and model drug substance/SLS 2:1), 4.9
hours (Akosoft 3103), 5.2 hours (model drug substance/SLS 1:1) and
6.4 hours (Tween 80/Kollidon VA64). Mean oral clearances (CL/F)
were comparable for treatments with HPC (7.01 Lkg.sup.-1h.sup.-1),
5% Captisol.RTM. (5.04 Lkg.sup.-1h.sup.-1), Tween 80/Kollidon VA64
(5.54 Lkg.sup.-1h.sup.-1) and Akosoft 3103 (4.70
Lkg.sup.-1h.sup.-1). As a consequence of the low AUC.sub.0-inf
values the two treatments with SLS show relatively high CL/F values
at 12 Lkg.sup.-1 h.sup.-1 (model drug substance/SLS 1:1) and 50
Lkg.sup.-1h.sup.-1 (model drug substance/SLS 2:1).
[0217] Mean volumes of distribution (V.sub.ZHF) observed were 29.6
Lkg.sup.-1 (HPC), 32.7 Lkg.sup.-1 (Akosoft 3103), 34.9 Lkg.sup.-1
(5% Captisol.RTM.) and 52.5 Lkg.sup.-1 (Tween 80/Kollidon VA64).
Again the values for the two SLS formulations were relatively
higher at 158 Lkg.sup.-1 and 352 Lkg.sup.-1.
[0218] Pharmacokinetic parameters estimated for the reference
solution were consistent with values found in a previous
formulation study performed on identical animals.
[0219] As supplement to these data other formulations have been
prepared including Captisol formulations: B (similar to the one in
the previous study), and three formulations prepared according to
the invention, formulation G, H and I. These formulations include
mixtures of glycerides. Formulations G, H and I (granulate in
capsule) have been manufactured by melt spraying.
Preparation of Test Formulation G, H and I According to the
Invention
Preparation of a Particulate Material--Melt-Spraying Process
Starting Materials
Kimol C8-50 (Mono-diglycerid on medium chain fatty acids)
(Cognis)
Viscoleo (medium chain triglycerides) (Grunau Illertissen)
Rylo MG 18 Pharma (Danisco Cultor)
Sodium lauryl sulfate (Millchem Limited)
Ascorbyl palmitate (Merck)
Model drug substance (the same substance is used throughout Example
5)
Lactose 350 M (DMV)
Equipment
[0220] Fluid bed Strea-1 (Aeromatic-Fielder) TABLE-US-00013
Compositions Material Formulation G g Formulation H g Formulation I
g Rylo MG 18 25.8 25.8 25.8 Viscoleo 21.2 21.2 21.2 Kirnol 21.2
21.2 21.2 Model drug 50.2 50.2 25.1 Lactose 350 M 202.1 248.1 275.7
SLS 46.0 -- -- Ascorbyl 1.8 1.8 1.8 palmitate
Process Conditions
[0221] The process conditions are similar for the formulation G, H
and I.
[0222] Rylo MG 18 was melted by heating to 70.degree. C. in a
pressure tank and the liquids Viscoleo and Kimol were added. The
melt was pumped through a heated tube (80.degree. C.) to the binary
nozzle in the fluid bed at a tank pressure of 0.2 Bar. The
atomizing air was heated to 140.degree. C. The inlet air
temperature of the fluid bed was 22.degree. C.
[0223] The melt was sprayed on fluidized material consisting of the
particulate materials, which include the model drug substance,
lactose and ascorbyl palmitate and for formulation G; sodium lauryl
sulfate. The flow rate was 20-30 g/min. The maximum product
temperature was 32.degree. C. at the end of the process.
Product Characteristic
[0224] Granular product with a particle size under 0.7 mm.
[0225] The product was filled into capsules (250 mg corresponding
to 30 mg base for Formulation G and H). 500 mg corresponding to 30
mg base for formulation I.
Example 6
Proof of Concept Based on Data from Development Project with
Nifedipine
[0226] Nifedipine is a yellow crystalline substance, practically
insoluble in water with a solubility of <56 mg/L at 25.degree.
C. It has a molecular weight of 346.3 and a melting range between
172-174.degree. C. The calculated log P is 2.5 and the experimental
measured value is 2.2. Nifedipine is rapidly and fully absorbed
after oral administration of the marketed products, however an
immediate release capsule only produce a bioavailability between 30
and 60%.
[0227] Proof of concept is based on a comparison of bioavailability
of different oral formulations with a solution of the drug
substance as reference, in dogs in a cross over design. A summary
is given below including detailed information on the melt spraying
process and tabletting (Treatment B and C)
Treatment A
[0228] Solution of nifedipine in PEG 400 TABLE-US-00014 Composition
Nifedipine 2% w/w PEG 400 98% w/w
1 ml per capsule (corresponds to 20 mg nifedipine) Treatment B
Plain tablet 20 mg Adalat.RTM. Bayer Treatment C
[0229] Tablets prepared from a particulate material produced
according to the present invention by melt spraying. Nifedipine is
contemplated to be present in PEG/poloxamer as a solid
solution.
Melt-Spraying Process
Starting Materials
Polyethyleneglycol 6000 (Hoechst)
Poloxamer 188 (BASF)
Nifedipine (Sigma-Aldrich)
Lactose 200 mesh (DMV)
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0230] 264.6 g PEG 6000 and 113.4 g Poloxamer 188 (70:30 w/w) were
melted by heating to 90.degree. C. in a pressure tank. 15.27 g drug
substance was dissolved in the melted carriers. The melt was pumped
through a heated tube (85.degree. C.) to the binary nozzle in the
fluid bed at a tank pressure of 1.6 Bar. The atomizing air was
heated to 140.degree. C. The inlet air temperature of the fluid bed
was 22.degree. C.
[0231] 308 g of melt was sprayed on 300 g fluidized lactose at a
flow rate of 17 g/min. The total yield was 608 g granulate. The
maximum product temperature was 37.degree. C. at the end of the
process.
Product Characteristic
[0232] Granular, free flowing product with a particle size under
0.7 mm TABLE-US-00015 Tablet composition Nifedipine 1.94% w/w PEG
6000 33.71% w/w Poloxamer 188 14.45% w/w Avicel PH101 48.90% w/w
Magnesium stearate 1.00% w/w
[0233] Magnesium stearate was blended with the granulate for 0.5
minutes in a Turbula-mixer.
Tabletting and Tablet Characteristics
The tabletting was performed on a single punch tabletting machine
Korsch EK0
Tablet shape 8 mm compound shape
Weight: 260 mg
Strength 5 mg
Mean tablet hardness (n=10) determined on a Schleuniger model 6D
was 97 N
Mean disintegration time was 11.3 minutes (Ph.Eur)
Weight variation (n=20) corresponded to RSD of 1.15%
Dosing 4 tablets (20 mg) in a capsule
Dosing
[0234] One dog was dosed with the 3 different formulations A, B and
C with 3 days between dosing. 2 ml of blood samples were taken at
pre-dose and 0.25, 0.5, 1, 1.5, 2, 4, 8 and 24 hours after
administration. The analysis of nifedipine was performed on
respective plasma samples.
Pharmacokinetic Results
[0235] The pharmacokinetic data are shown in the Table below
TABLE-US-00016 Formulation A B C T.sub.max (h) 0.5 0.5 1.0
C.sub.max (ng/ml) 66.6 22.0 61.0 AUC.sub.0-inf.sup.a (ngh/ml) 172.2
22.2 53.1 F.sub.rel.sup.b (%) 100 12.9 30.8 Calculated as
.sup.aAUC.sub.last + C.sub.last/.lamda..sub.z;
.sup.bAUC.sub.0-inf,po * D.sub.ref/(AUC.sub.0-inf,ref *
D.sub.po)
[0236] The bioavailability F.sub.rel is calculated relative to
formulation A, representing a solution of nifedipine in PEG 400.
The corresponding plasma profiles are shown in FIG. 7.
Conclusion
[0237] Apparently the solid solution of nifedipine in
PEG6000/Poloxamer (formulation C) results in significant higher
bioavailability compared to a plain tablet formulation
(Adalat).
Example 7
Neusilin as Absorption Material in Controlled Agglomeration
Background
[0238] It is established that magnesium aluminium silicate
(Carrisorb, Gelsorp, Magnabite) is suitable in absorption of
liquids and commonly used as a viscosity increasing, a tablet
disintegrant and a tablet binding agent.
[0239] Neusilin (Fuji Chemical Industries) is a magnesium
aluminometasilicate based on a polymeric reaction of sodium
silicate having a siloxane structure (U.S. Pat. No. 3,959,444) in
combination with a mixture or sodium aluminate and magnesium
salts.
[0240] Neusilin US2 is a spray dried free flowing material with a
particle size of approx. 80 .mu.m and a specific surface area of
300 m.sup.2/g.
[0241] Two experiments (A and B) have been performed where PEG 6000
is sprayed on fluidized Neusilin in a fluid bed Strea-1.
[0242] Experiment A is performed under conditions of controlled
agglomeration keeping the temperature difference over 10.degree. C.
between the product and the melting point of PEG 6000 (59.degree.
C.).
[0243] Experiment B is performed under heating condition of the
inlet air (50-70.degree. C.) resulting in a product temperature
under the 10.degree. C. temperature difference.
Experiment A
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0244] 1000 g PEG 6000 was melted by heating to 90.degree. C. in a
pressure tank. The melt was pumped through a heated tube
(85.degree. C.) to the binary nozzle in the fluid bed at a tank
pressure of 1.5 Bar. The atomizing air was heated to 140.degree. C.
The inlet air temperature of the fluid bed was 22.degree. C.
[0245] 584 g of melt was sprayed on 150 g fluidized Neusilin US2 at
a flow rate of 19 g/min. The total yield was 734 g granulate. The
maximum product temperature was 45.degree. C. at the end of the
process. The concentration of PEG 6000 in the particulate material
obtained was 79.6% w/w.
Product Characteristic
[0246] Granular, free flowing product with a particle size d.sub.gw
of 409 .mu.m. TABLE-US-00017 Tablet composition PEG 6000 79.6%
Neusilin 20.4%
Tabletting and Tablet Characteristics
[0247] The tabletting was performed on a single punch tabletting
machine Korsch EK0. It was not necessary to add further excipients
for the tabletting procedure.
Tablet shape 8 mm compound cup
Weight: 200 mg
Mean tablet hardness (n=10) determined on a Schleuniger model 6D
was 48.6 N
Mean disintegration time was 22.4 minutes (Ph.Eur)
Weight variation (n=20) corresponded to RSD of 0.6%
Experiment B
Equipment
Fluid bed Strea-1 (Aeromatic-Fielder)
Process Conditions
[0248] 800 g PEG 6000 was melted by heating to 90.degree. C. in a
pressure tank. The melt was pumped through a heated tube
(85.degree. C.) to the binary nozzle in the fluid bed at a tank
pressure of 1.5 Bar. The atomizing air was heated to 140.degree. C.
The inlet air temperature of the fluid bed was 60.degree. C.
[0249] 505 g of melt was sprayed on 150 g fluidized Neusilin US2 at
a flow rate of 19 g/min. The total yield was 655 g granulate. The
maximum product temperature was 58.degree. C. at the end of the
process.
Product Characteristic
[0250] Granular, free flowing product with a particle size under
0.7 mm. TABLE-US-00018 Tablet composition PEG 6000 77.1% Neusilin
22.9%
Tabletting and Tablet Characteristics
[0251] Tabletting was not possible due to adhesion to the
punches.
Conclusion
[0252] Neusilin US2 acts as an absorption agent for the melted
carrier sprayed on the fluidized material.
[0253] Surprisingly high amount of carrier was applicable
corresponding to a total amount of carrier exceeding 80% without
getting uncontrolled agglomeration. In Experiment A, the
temperature difference between product and melting point of the
carrier exceeded 10.degree. C. Further, direct tabletting of the
product without adding lubricant was successfully performed.
[0254] Increasing the inlet temperature of the fluidized bed
(Experiment B) exceeding the temperature limits for controlled
agglomeration (recognized for the traditionally employed
excipients) did not result in un-controlled agglomeration as
expected. This is most likely due to the high absorption capacity
of Neusilin preventing free surface liquid to form bondings between
the fluidized particles. However, uncontrolled agglomeration
occurred at the end of the process (77.1% PEG 6000). Direct
compression of the product was not possible due to adhesion to the
punches indicating surface free PEG in the agglomerates, which
might be due to the elevated product temperature in the
agglomeration process.
[0255] To sum up, it is possible to obtain controlled agglomeration
even in those cases where no or only a small temperature difference
is present between the carrier and the second composition. This
applies especially for substances like Neusilin and the like.
Example 8
Lubricant Effect of Neusilin in Comparison with Magnesium Stearate
and Aerosil 200
[0256] A sticky granulate was produced by controlled agglomeration.
PEG 1500 (melting range of from about 44 to about 48.degree. C.)
was applied on lactose 200 mesh in a fluid bed Strea-1. The
composition of the product was as follows: TABLE-US-00019 Lactose
200 mesh 300 g PEG 1500 200 g
[0257] The granulate was sieved through a 0.71 mm mesh size.
[0258] A part of the granulate was blended with the different
substances for 3 minutes in a Turbula mixer in order to determine
any lubricating effect. Two of the substances used, namely
magnesium stearate and Aerosil, are known lubricants. The
substances employed were:
Neusilin ULF2 (Fuji Chemical Industries)
Magnesium stearate (Magnesia GmbH)
Aerosil 200 (colloidal silicon dioxide), (Degussa AG)
Tablets were produced on a single punch tabletting machine Korsch
EK0, instrumented with force transducer on the filling device
measuring the force to push off the tablet from the lower
punch.
Tablet diameter 8 mm. Tablet shape: Compound cup
Tablet weight: 200 mg
[0259] The results are summarised in the Table below TABLE-US-00020
Adhesion to tablet Lubricant Conc. % punches Mean Push off force N
Neusilin 2 no 4.5 4 no 1.1 Mg-stearate 1 Adhesion n.m. Aerosil 200
0.5 Adhesion n.m 1 Adhesion n.m
Conclusion
[0260] Neusilin and Aerosil provided excellent flowability to the
sticky granular product, whereas magnesium stearate did not have
this effect. Aerosil is normally used as lubricant in the
concentrations below 0.5% and is primarily used to improve the
flowability of cohesive materials.
[0261] The anti-adhesive property of Neusilin is superior to both
magnesium stearate and Aerosil. Granules blended with either 2 or
4% of Neusilin was compressed without any adhesion to the punches.
As shown in the Table the adhesion to the lower punch was
significantly decreased when increasing the concentration of
Neusilin from 2 to 4%. The push off force was not monitored (n.m.)
for the other lubricants since compression of tablets was not
possible due to immediately adhesion to the punches.
[0262] Thus, the results demonstrate that Neusilin is an excellent
lubricant having anti-adhesive properties.
* * * * *